Pyridazinone compounds and methods for the treatment of cystic fibrosis

ABSTRACT

The invention relates to a compound of having the following formulae and methods of treating cystic fibrosis:

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/778,870, filed on Mar. 13, 2013. The entire teachings of the aboveapplication are incorporated herein by reference.

BACKGROUND

Cystic fibrosis (CF) is a lethal, recessive, genetic disease affectingapproximately 1 in 2500 live births among Caucasians. (Cohen-CymberknohM, Shoseyov D, Kerem E. Managing cystic fibrosis: strategies thatincrease life expectancy and improve quality of life. Am J Respir CritCare Med (2011); 183: 1463-1471; Boat T F, Welsh M J and Beaudet A L.Cystic fibrosis. (1989) IN “The Metabolic Basis of Inherited Disease” (CL Scriver, A L Beaudet, W S Sly and D Valee, eds.), 6^(th) Ed., pp.2649-2680. McGraw-Hill, New York. Approximately 1 in 25 persons arecarriers of the genetic defect associated with disease. The majorsymptoms of cystic fibrosis include chronic pulmonary disease,pancreatic exocrine insufficiency, infertility in males, and elevatedsweat electrolyte levels. The symptoms are consistent with cysticfibrosis being an exocrine disorder. (Hantash F: U.S. Patent ApplicationNo. 20060057593. Method for detecting cystic fibrosis).

The CF gene codes for a cAMPPKA-dependent, ATP-requiring, membrane-boundchloride ion channel known as CFTR (cystic fibrosis transmembraneconductance regulator), and is, generally localized to the apicalmembranes of many secreting. There are currently over 1700 knownmutations affecting CFTR, many of which give rise to a diseasephenotype. Around 75% of CF alleles contain the ΔF508 mutation in whicha triplet codon has been lost, leading to a missing phenylalanine atposition 508 in the protein. This altered protein fails to be traffickedto the correct location in the cell and is generally destroyed by theproteasome. The small amount that does reach the correct locationfunctions poorly. (Cutbert A W. New horizons in the treatment of cysticfibrosis. British J Pharm, (2011), 163: 173-183).

Mutations in the CFTR gene result in absence or dysfunction of theprotein that regulates ion transport across the apical membrane at thesurface of certain epithelia. Although CFTR functions mainly as achloride channel, it has many other roles, including inhibition ofsodium transport through the epithelial sodium channel, regulation ofthe outwardly rectifying chloride channel, ATP channels, intracellularvesicle transport, and inhibition of endogenous calcium-activatedchloride channels. CFTR is also involved in bicarbonatechlorideexchange. A deficiency in bicarbonate secretion leads to poor solubilityand aggregation of luminal mucins. Obstruction of intrapancreatic ductswith thickened secretions causes autolysis of pancreatic tissue withreplacement of the body of the pancreas with fat, leading to pancreaticinsufficiency with subsequent malnutrition. In the lungs, CFTRdysfunction leads to airway surface liquid (ASL) depletion and thickenedand viscous mucus that adheres to airway surfaces. The result isdecreased mucociliary clearance (MCC) and impaired host defenses.Dehydrated, thickened secretions lead to endobronchial infection with alimited spectrum of distinctive bacteria, mainly Staphylococcus aureusand Pseudomonas aeruginosa, Deficiency in bicarbonate secretion due toloss of CFTR function also results in a lower pH at the airway surfacewhich impairs anti-bacterial killing activity and increasessusceptibility to infection. An exaggerated inflammatory response inresponse to chronic lung infections leads to the development ofbronchiectasis and progressive obstructive airways disease. Pulmonaryinsufficiency is responsible for most CF-related deaths.(Cohen-Cymberknoh M, Shoseyov D, Kerem E. Managing cystic fibrosis:strategies that increase life expectancy and improve quality of life. AmJ Respir Crit Care Med (2011); 183: 1463-1471).

The prognosis for the treatment of CF has improved over the last 40years. This was achieved by improving pancreatic enzyme supplements,drugs designed to treat pulmonary infection, reduce inflammation andenhance mucociliary clearance. Currently the therapeutic challenges areto correct the biochemical defect of CF and to identify effectivetreatments for chronic respiratory infection. (Frerichs C, Smyth A.Treatment strategies for cystic fibrosis: what's in the pipeline?Pharmacotherapty (2009), 10: 1191-1202).

SUMMARY

The invention relates to a compound of Formula I and methods of treatingCFTR (cystic fibrosis transmembrane conductance regulator) mediateddiseases, in particular cystic fibrosis, comprising the step ofadministering a therapeutically effective amount of a compound ofFormula I to a patient in need thereof:

-   A₁ is absent, —[C(R100)(R101)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —S(O)₂—, carbocycle, substituted carbocycle,    heterocycle, substituted heterocycle, aromatic, substituted    aromatic, heteroaromatic or substituted heteroaromatic;-   wherein n is 0, 1, 2, 3, 4, 5, 6 or 7;-   wherein each R₁₀₀ and R₁₀₁ is hydrogen, deuterium, halogen, alkyl,    substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl; alternatively two    of R₁₀₀ and R₁₀₁ groups together with the atoms to which they are    attached and any intervening atoms may form an additional optionally    substituted, 3, 4, 5, 6 or 7 membered ring;-   A₂ is absent or —[C(R100)(R101)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    —S(O)₂R₁₀₀, —S(O)R₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁),-   A₃ is a bond or —[C(R100)(R101)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    S(O)₂R₁₀₀, S(O)R₁₀₀, S(O)₂N(R₁₀₀)(R₁₀₁);-   Cy₁ is absent, an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   Cy₂ is an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings; and-   Cy₃ is absent, an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a compound of Formula I and methods of treatingcystic fibrosis comprising the step of administering a therapeuticallyeffective amount of a compound of Formula I to a patient in needthereof:

-   A₁ is absent, —[C(R₁₀₀)(R₁₀₁)]_(n)—, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —S(O)₂N(R₁₀₀)—, —S(O)₂—, carbocycle, substituted    carbocycle, heterocycle, substituted heterocycle, aromatic,    substituted aromatic, heteroaromatic or substituted heteroaromatic;-   wherein n is 0, 1, 2, 3, 4, 5, 6 or 7;-   wherein each R₁₀₀ and R₁₀₁ is hydrogen, deuterium, halogen, alkyl,    substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl; alternatively two    of R₁₀₀ and R₁₀₁ groups together with the atoms to which they are    attached and any intervening atoms may form an additional optionally    substituted, 3, 4, 5, 6 or 7 membered ring;-   A₂ is absent or —[C(R100)(R101)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    —S(O)₂R₁₀₀, —S(O)R₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁);-   A₃ is absent or —[C(R100)(R101)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    S(O)₂R₁₀₀, S(O)R₁₀₀, S(O)₂N(R₁₀₀)(R₁₀₁);-   Cy₁ is absent, an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   Cy₂ is an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings; and-   Cy₃ is absent, an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings.

In a preferred embodiment, the invention relates to a compound havingthe formula:

-   wherein each X is independently, —CR₁₀₀— or —N—.

In a preferred embodiment, the invention relates to a compound wherein Xis —C(R₁₀₀) and

-   wherein R₁₀₀ is preferred as H, halogen, alkoxy or alkyl.

In a preferred embodiment the invention relates to a compound having theformula:

-   wherein each Y is independently —CR₁₀₀—, —NR₁₀₀, —N, —O or —S.

In a preferred embodiment, the invention relates to a compound havingthe formula:

-   wherein p is 0, 1, 2, 3 or 4; and-   wherein R₈ is hydrogen, deuterium, alkyl, substituted alkyl,    alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,    aliphatic, substituted aliphatic, carbocycle, substituted    carbocycle, aryl, substituted aryl, heterocyclyl, substituted    heterocyclyl, heteroaryl, or substituted heteroaryl; and-   R₉ is independently selected from hydrogen, deuterium, halo, alkyl,    substituted alkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, aliphatic, substituted aliphatic, carbocycle,    substituted carbocycle, aryl, substituted aryl, heterocyclyl,    substituted heterocyclyl, heteroaryl, or substituted heteroaryl    —OR₁₀₀, —NR₁₀₀R₁₀₁, —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁,    —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀, —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁,    —CF₃, —CN, —NO₂, —N₃.

In a preferred embodiment, the invention relates to a compound whereinR₈ is C₁-C₄ alkyl.

In a preferred embodiment, the invention relates to a compound whereinR₉ is H, alkyl, alkoxy or halogen.

In a preferred embodiment, the invention relates to a compound, whereinA₃ is H and Cy₁ is absent.

In a preferred embodiment, the invention relates to a compound havingthe formula:

In a preferred embodiment, the invention relates to a compound whereinA₁ is carbocycle, substituted carbocycle, heterocycle, substitutedheterocycle, aromatic, substituted aromatic, heteroaromatic, substitutedheteroaromatic.

In a preferred embodiment, the invention relates to a compound havingthe formula:

-   wherein m is 0, 1, 2, 3, 4 or 5; and-   each R₂ is independently selected from hydrogen, deuterium, halogen,    alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, or substituted heteroaryl —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;-   alternatively two R₂ together with the atoms to which they are    attached may form an optionally substituted 3, 4, 5, 6 or 7 membered    ring, preferably a cycloalkyl, substituted cycloalkyl, heterocycle,    substituted heterocycle, aryl, substituted aryl, heteroaryl or    substituted heteroaryl group.

In a preferred embodiment, the invention relates to a compound havingthe formula:

-   wherein each W is independently CH, CR₁₀₀, C(O), N, NR₁₀₀, O, S, SO,    or SO₂;-   each R₃ and R₄ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃; and-   wherein ------ represents a single or double bond.

In a preferred embodiment, the invention relates to a compound whereinA₁ is C(R₁₀₀)(R₁₀₁) and A₂ is —C(O)N(R₁₀₀)—.

In a preferred embodiment, the invention relates to a compound whereinA₃ is absent, —[C(R100)(R101)]n-, —C(O)—, —C(O)N(R₁₀₀)— or—C(O)N(R₁₀₀)(R₁₀₁).

In a preferred embodiment, the invention relates to a compound whereinCy1 is selected from:

-   wherein q is 0, 1, 2, 3, 4 or 5; each R₁₀₂ is hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    carbocycle, substituted carbocycle, aryl, substituted aryl, —OR₁₀₀,    —SR₁₀₀, —NR₁₀₀R₁₀₁, —C(O)R₁₀₀, —C(O)OR₁₀₀,-   —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀, —S(O)R₁₀₀, —SR₁₀₀,    —S(O)₂N(R₁₀₀)R₁₀₁—CF₃, —CN,-   —NO₂, —N₃; alternatively two of R₁₀₂ groups together with the atoms    to which they are attached and any intervening atoms may form an    additional optionally substituted 3, 4, 5, 6 or 7 membered ring; and-   R₁₀₃ is hydrogen, deuterium, alkyl, substituted alkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl.

In a preferred embodiment, the invention relates to a compound whereinCy2 is selected from:

-   wherein q is 0, 1, 2, 3, 4 or 5;-   each R₁₀₂ is independently hydrogen, deuterium, halogen, alkyl,    substituted alkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, aliphatic, substituted aliphatic, carbocycle,    substituted carbocycle, aryl, substituted aryl, —OR₁₀₀, —SR₁₀₀,    —NR₁₀₀R₁₀₁, —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁,    —S(O)₂R₁₀₀, —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁—CF₃, —CN, —NO₂,    —N₃; alternatively two of R₁₀₂ groups together with the atoms to    which they are attached and any intervening atoms may form an    additional optionally substituted 3, 4, 5, 6 or 7 membered ring; and-   R₁₀₅ is hydrogen, deuterium, alkyl, substituted alkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl.

In one embodiment, the invention relates to a compound of Formula II:

-   or a pharmaceutically acceptable salt, ester or prodrug thereof;-   wherein    represents a single or double bond;-   m is 0, 1, 2, 3 or 4;-   d is 0, 1 or 2;-   X₁₀ is CH, CH₂, S, N or O;-   Cy₁ is absent, an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   Cy₂ is an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;    preferably, Cy2 is a C₅-C₇ aryl or heteroaryl; Preferably Cy2 is    substituted with —OR₂₀₀, —SR₂₀₀, —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂,    —NC(O)R₂₀₀, —S(O)₂R₂₀₀ wherein R₂₀₀ is hydrogen, C₁-C₆ alkyl, C₂-C₆    alkenyl, or C₂-C₆ alkynyl;-   A₁ is absent, —[C(R₁₀₀)(R₁₀₁)]_(n)—, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —S(O)₂N(R₁₀₀)—, —S(O)₂—, —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p, carbocycle, substituted    carbocycle, heterocycle, substituted heterocycle, aromatic,    substituted aromatic, heteroaromatic or substituted heteroaromatic;    wherein n is 0, 1, 2, 3, 4, 5, 6 or 7;-   wherein each R₁₀₀ and R₁₀₁ is hydrogen, deuterium, halogen, alkyl,    substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl, —OR₂₀₀, —SR₂₀₀,    —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂, —NC(O)R₂₀₀, —S(O)₂R₂₀₀ wherein R₂₀₀ is    hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;    alternatively two of R₁₀₀ and R₁₀₁ groups together with the atoms to    which they are attached and any intervening atoms may form an    additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;    Preferably each R₁₀₀ and R₁₀₁ is independently selected from C₁-C₈    alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl and C₃-C₈ cycloalkyl;-   A₂ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    —S(O)₂R₁₀₀, —S(O)R₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁), —[C(R₂₅)(R₂₆)]n—,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   A₃ is absent or —[C(R100)(R101)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    S(O)₂R₁₀₀, S(O)R₁₀₀, S(O)₂N(R₁₀₀)(R₁₀₁), —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   A₄ is absent or —[C(R₂₅)(R₂₆)]n-, —[C(R₂₅)(R₂₆)]n-,    C═C—[C(R₂₇)(R₂₈)]p, or —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   wherein each R₂₅, R₂₆, R₂₇ and R₂₈ is independently selected    hydrogen, deuterium, halogen, alkyl, substituted alkyl, heteroalkyl,    substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, aliphatic, substituted aliphatic, aryl and    substituted aryl; alternatively two of R₂₅, R₂₆, R₂₇ and R₂₈ groups    together with the atoms to which they are attached and any    intervening atoms may form an additional optionally substituted, 3,    4, 5, 6 or 7 membered ring; preferably a cyclopropyl group;-   p is 0, 1, 2, 3, 4, 5, 6, or 7;-   R₂ is independently selected from hydrogen, deuterium, halogen,    alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, or substituted heteroaryl —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;    alternatively two R₂ together with the atoms to which they are    attached may form an optionally substituted 3, 4, 5, 6 or 7 membered    ring, preferably a cycloalkyl, substituted cycloalkyl, heterocycle,    substituted heterocycle, aryl, substituted aryl, heteroaryl or    substituted heteroaryl group; and,-   each R₃ and R₄ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃.

In one embodiment, the invention relates to a compound of Formula IIA:

-   or a pharmaceutically acceptable salt, ester or prodrug thereof;-   wherein    represents a single or double bond;-   m is 0, 1, 2, 3 or 4;-   t is 0, 1, 2 or 3;-   X₁₀ is CH, CH₂, O, N or S;-   Cy₁ is absent, an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   A₁ is absent, —[C(R₁₀₀)(R₁₀₁)]_(n)—, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —S(O)₂N(R₁₀₀)—, —S(O)₂—, —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p, carbocycle, substituted    carbocycle, heterocycle, substituted heterocycle, aromatic,    substituted aromatic, heteroaromatic or substituted heteroaromatic;    wherein n is 0, 1, 2, 3, 4, 5, 6 or 7;-   wherein each R₁₀₀ and R₁₀₁ is hydrogen, deuterium, halogen, alkyl,    substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl, —OR₂₀₀, —SR₂₀₀,    —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂, —NC(O)R₂₀₀, —S(O)₂R₂₀₀ wherein R₂₀₀ is    hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;    alternatively two of R₁₀₀ and R₁₀₁ groups together with the atoms to    which they are attached and any intervening atoms may form an    additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;-   A₂ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    —S(O)₂R₁₀₀, —S(O)R₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁), —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   A₃ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    S(O)₂R₁₀₀, S(O)R₁₀₀, S(O)₂N(R₁₀₀)(R₁₀₁), —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   A₄ is absent or —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   wherein each R₂₅, R₂₆, R₂₇ and R₂₈ is hydrogen, deuterium, halogen,    alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl,    alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,    aliphatic, substituted aliphatic, aryl and substituted aryl;    alternatively two of R₂₅, R₂₆, R₂₇ and R₂₈ groups together with the    atoms to which they are attached and any intervening atoms may form    an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;    preferably a cyclopropyl group;-   p is 0, 1, 2, 3, 4, 5, 6, or 7;-   R₂ is independently selected from hydrogen, deuterium, halogen,    alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, or substituted heteroaryl —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;    alternatively two R₂ together with the atoms to which they are    attached may form an optionally substituted 3, 4, 5, 6 or 7 membered    ring, preferably a cycloalkyl, substituted cycloalkyl, heterocycle,    substituted heterocycle, aryl, substituted aryl, heteroaryl or    substituted heteroaryl group;-   each R₃ and R₄ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;-   R₁₂₀ is selected from hydrogen, deuterium, halogen, alkyl,    substituted alkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, aliphatic, substituted aliphatic, aryl,    substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃; and,-   each R₁₂₁ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃.

In one embodiment, the invention relates to a compound of Formula IIB:

-   or a pharmaceutically acceptable salt, ester or prodrug thereof;-   wherein    represents a single or double bond;-   m is 0, 1, 2, 3 or 4;-   t is 0, 1, 2 or 3;-   X₁₀ is CH, CH₂, N, S or O;-   A₁ is absent, —[C(R₁₀₀)(R₁₀₁)]_(n)—, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —S(O)₂N(R₁₀₀)—, —S(O)₂—, —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C[C(R₂₇)(R₂₈)]p, carbocycle, substituted    carbocycle, heterocycle, substituted heterocycle, aromatic,    substituted aromatic, heteroaromatic or substituted heteroaromatic;    wherein n is 0, 1, 2, 3, 4, 5, 6 or 7;-   wherein each R₁₀₀ and R₁₀₁ is hydrogen, deuterium, halogen, alkyl,    substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl, OR₂₀₀, —SR₂₀₀,    —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂, —NC(O)R₂₀₀, —S(O)₂R₂₀₀ wherein R₂₀₀ is    hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;    alternatively two of R₁₀₀ and R₁₀₁ groups together with the atoms to    which they are attached and any intervening atoms may form an    additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;-   A₂ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    —S(O)₂R₁₀₀, —S(O)R₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁), —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   A₃ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    S(O)₂R₁₀₀, S(O)R₁₀₀, S(O)₂N(R₁₀₀)(R₁₀₁), —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   A₄ is absent or —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   wherein each R₂₅, R₂₆, R₂₇ and R₂₈ is hydrogen, deuterium, halogen,    alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl,    alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,    aliphatic, substituted aliphatic, aryl and substituted aryl;    alternatively two of R₂₅, R₂₆, R₂₇ and R₂₈ groups together with the    atoms to which they are attached and any intervening atoms may form    an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;    preferably a cyclopropyl group;-   p is 0, 1, 2, 3, 4, 5, 6, or 7;-   R₂ is independently selected from hydrogen, deuterium, halogen,    alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, or substituted heteroaryl —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;    alternatively two R₂ together with the atoms to which they are    attached may form an optionally substituted 3, 4, 5, 6 or 7 membered    ring, preferably a cycloalkyl, substituted cycloalkyl, heterocycle,    substituted heterocycle, aryl, substituted aryl, heteroaryl or    substituted heteroaryl group;-   each R₃ and R₄ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;-   R₁₂₀ is selected from hydrogen, deuterium, halogen, alkyl,    substituted alkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, aliphatic, substituted aliphatic, aryl,    substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;-   each R₁₂₁ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;-   R₁₂₂ is halogen or —CN; and,-   each R₁₂₃ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃.

In one embodiment, the invention relates to a compound of Formula IIC:

-   or a pharmaceutically acceptable salt, ester or prodrug thereof;-   wherein    represents a single or double bond;-   m is 0, 1, 2, 3 or 4;-   t is 0, 1, 2 or 3;-   R₂ is independently selected from hydrogen, deuterium, halogen,    alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, or substituted heteroaryl —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;    alternatively two R₂ together with the atoms to which they are    attached may form an optionally substituted 3, 4, 5, 6 or 7 membered    ring, preferably a cycloalkyl, substituted cycloalkyl, heterocycle,    substituted heterocycle, aryl, substituted aryl, heteroaryl or    substituted heteroaryl group;-   each R₃ and R₄ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;-   R₁₂₀ is selected from hydrogen, deuterium, halogen, alkyl,    substituted alkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, aliphatic, substituted aliphatic, aryl,    substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;-   each R₁₂₁ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;-   R₁₂₂ is halogen or —CN; and,-   each R₁₂₃ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;-   R₁₂₅ is alkyl or substituted alkyl;-   wherein each R₁₀₀ and R₁₀₁ is hydrogen, deuterium, halogen, alkyl,    substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl, OR₂₀₀, —SR₂₀₀,    —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂, —NC(O)R₂₀₀, —S(O)₂R₂₀₀ wherein R₂₀₀ is    hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;    alternatively two of R₁₀₀ and R₁₀₁ groups together with the atoms to    which they are attached and any intervening atoms may form an    additional optionally substituted, 3, 4, 5, 6 or 7 membered ring.

In one embodiment, the invention relates to a compound of Formula IID:

-   or a pharmaceutically acceptable salt, ester or prodrug thereof;-   wherein    represents a single or double bond;-   m is 0, 1, 2, 3 or 4;-   t is 0, 1, 2 or 3;-   R₂ is independently selected from hydrogen, deuterium, halogen,    alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, or substituted heteroaryl —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;    alternatively two R₂ together with the atoms to which they are    attached may form an optionally substituted 3, 4, 5, 6 or 7 membered    ring, preferably a cycloalkyl, substituted cycloalkyl, heterocycle,    substituted heterocycle, aryl, substituted aryl, heteroaryl or    substituted heteroaryl group;-   each R₃ and R₄ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;-   R₁₂₀ is selected from hydrogen, deuterium, halogen, alkyl,    substituted alkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, aliphatic, substituted aliphatic, aryl,    substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;-   each R₁₂₁ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;-   R₁₂₂ is halogen, —CN, SO₂NH₂, CONH₂, CO₂H, —CH₃, OCH₃, —OR₁₀₀;-   each R₁₂₃ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃; and,-   R₁₂₅ is alkyl or substituted alkyl;-   wherein each R₁₀₀ and R₁₀₁ is hydrogen, deuterium, halogen, alkyl,    substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl, —OR₂₀₀, —SR₂₀₀,    —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂, —NC(O)R₂₀₀, —S(O)₂R₂₀₀ wherein R₂₀₀ is    hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;    alternatively two of R₁₀₀ and R₁₀₁ groups together with the atoms to    which they are attached and any intervening atoms may form an    additional optionally substituted, 3, 4, 5, 6 or 7 membered ring.

In one embodiment, the invention relates to a compound of Formula IV:

-   or a pharmaceutically acceptable salt, ester or prodrug thereof;-   wherein    represents a single or double bond;-   m is 0, 1, 2, 3 or 4;-   Cy₁ is absent, an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   Cy₂ is an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   Cy₄ is an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   A₁ is absent, —[C(R₁₀₀)(R₁₀₁)]_(n)—, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —S(O)₂N(R₁₀₀)—, —S(O)₂—, —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    [C(R₂₅)(R₂₆)]n-C≡C[C(R₂₇)(R₂₈)]p, carbocycle, substituted    carbocycle, heterocycle, substituted heterocycle, aromatic,    substituted aromatic, heteroaromatic or substituted heteroaromatic;    wherein n is 0, 1, 2, 3, 4, 5, 6 or 7;-   wherein each R₁₀₀ and R₁₀₁ is hydrogen, deuterium, halogen, alkyl,    substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl, —OR₂₀₀, —SR₂₀₀,    —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂, —NC(O)R₂₀₀, —S(O)₂R₂₀₀ wherein R₂₀₀ is    hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;    alternatively two of R₁₀₀ and R₁₀₁ groups together with the atoms to    which they are attached and any intervening atoms may form an    additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;-   A₂ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    —S(O)₂R₁₀₀, —S(O)R₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁), —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   A₃ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    S(O)₂R₁₀₀, S(O)R₁₀₀, S(O)₂N(R₁₀₀)(R₁₀₁), —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   A₄ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   wherein each R₂₅, R₂₆, R₂₇ and R₂₈ is hydrogen, deuterium, halogen,    alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl,    alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,    aliphatic, substituted aliphatic, aryl and substituted aryl;    alternatively two of R₂₅, R₂₆, R₂₇ and R₂₈ groups together with the    atoms to which they are attached and any intervening atoms may form    an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;    preferably a cyclopropyl group;-   R₁₂₆ is selected from hydrogen, halogen, optionally substituted    C₁-C₈ alkyl, —OR₁₀₀, —SR₁₀₀, N(R₁₀₀)(R₁₀₁) and S(O)₂C₁₋₈alkyl;-   p is 0, 1, 2, 3, 4, 5, 6, or 7;-   R₂ is independently selected from hydrogen, deuterium, halogen,    alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, or substituted heteroaryl —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;    alternatively two R₂ together with the atoms to which they are    attached may form an optionally substituted 3, 4, 5, 6 or 7 membered    ring, preferably a cycloalkyl, substituted cycloalkyl, heterocycle,    substituted heterocycle, aryl, substituted aryl, heteroaryl or    substituted heteroaryl group;-   each R₃ and R₄ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;-   each X₁₁ and X₁₂ is selected from absent, —C(R₁₁₀)(R₁₁₁)—, —N(R₁₁₀),    —S—, —O—, and S(O)₂; wherein at least one of X₁₁ and X₁₂ is present;    each R₁₁₀ and R₁₁₁ is independently selected from absent, hydrogen,    deuterium, halogen, alkyl, substituted alkyl, heteroalkyl,    substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, aliphatic, substituted aliphatic, aryl and    substituted aryl; and,-   each X₁₃, X₁₄, X₁₅, and X₁₆ is independently selected from —C— and    —N—.

In one embodiment, the invention relates to a compound of Formula IVA,IVB, IVC, IVD or IVE:

-   or a pharmaceutically acceptable salt, ester or prodrug thereof;-   wherein    represents a single or double bond;-   m is 0, 1, 2, 3 or 4;-   W₁ is CH, CH₂, CR₁₀₀, C(O), N, NR₁₀₀, O, S, SO, or SO₂; preferably O    or N; more preferably W₁ is N;-   W₂ is O, S, N, CH, CH₂; preferably S or O; more preferably W₂ is O;-   Cy₁ is absent, an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   Cy₂ is an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   A₁ is absent, —[C(R₁₀₀)(R₁₀₁)]_(n)—, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —S(O)₂N(R₁₀₀)—, —S(O)₂—, —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]_(p), carbocycle, substituted    carbocycle, heterocycle, substituted heterocycle, aromatic,    substituted aromatic, heteroaromatic or substituted heteroaromatic;    wherein n is 0, 1, 2, 3, 4, 5, 6 or 7;-   wherein each R₁₀₀ and R₁₀₁ is hydrogen, deuterium, halogen, alkyl,    substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl, —OR₂₀₀, —SR₂₀₀,    —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂, —NC(O)R₂₀₀, —S(O)₂R₂₀₀ wherein R₂₀₀ is    hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;    alternatively two of R₁₀₀ and R₁₀₁ groups together with the atoms to    which they are attached and any intervening atoms may form an    additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;-   A₂ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    —S(O)₂R₁₀₀, —S(O)R₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁), —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   A₃ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    S(O)₂R₁₀₀, S(O)R₁₀₀, S(O)₂N(R₁₀₀)(R₁₀₁), —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   A₄ is absent or —[C(R₂₅)(R₂₆)]n-,    —[C(R₂₅)(R₂₆)]n-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]n-C≡C—[C(R₂₇)(R₂₈)]p;-   wherein each R₂₅, R₂₆, R₂₇ and R₂₈ is hydrogen, deuterium, halogen,    alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl,    alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,    aliphatic, substituted aliphatic, aryl, substituted aryl, —OR₁₀₀,    —SR₁₀₀, —NR₁₀₀R₁₀₁, —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁,    —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀, —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁,    —CF₃, —CN, —NO₂, and —N₃; alternatively two of R₂₅, R₂₆, R₂₇ and R₂₈    groups together with the atoms to which they are attached and any    intervening atoms may form an additional optionally substituted, 3,    4, 5, 6 or 7 membered ring; preferably a cyclopropyl group;-   R₁₂₆ is selected from hydrogen, halogen, optionally substituted    C₁-C₈ alkyl, —OR₁₀₀, —SR₁₀₀, N(R₁₀₀)(R₁₀₁) and S(O)₂C₁₋₈ alkyl;-   p is 0, 1, 2, 3, 4, 5, 6, or 7;-   R₂ is independently selected from hydrogen, deuterium, halogen,    alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, or substituted heteroaryl —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;    alternatively two R₂ together with the atoms to which they are    attached may form an optionally substituted 3, 4, 5, 6 or 7 membered    ring, preferably a cycloalkyl, substituted cycloalkyl, heterocycle,    substituted heterocycle, aryl, substituted aryl, heteroaryl or    substituted heteroaryl group; and,-   each R₃ and R₄ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃.

In one embodiment, the invention relates to a compound of Formula V:

-   or a pharmaceutically acceptable salt, ester or prodrug thereof;-   wherein    represents a single or double bond;-   m is 0, 1, 2, 3 or 4;-   Cy₁ is absent, an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   Cy₂ is an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   A₁ is absent, —[C(R₁₀₀)(R₁₀₁)]_(n)—, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —S(O)₂N(R₁₀₀)—, —S(O)₂, carbocycle, substituted    carbocycle, heterocycle, substituted heterocycle, aromatic,    substituted aromatic, heteroaromatic or substituted heteroaromatic;    wherein n is 0, 1, 2, 3, 4, 5, 6 or 7; preferably, Cy₂ is a C₅-C₇    aryl or heteroaryl; Preferably Cy₂ is substituted with —OR₂₀₀,    —SR₂₀₀, —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂, —NC(O)R₂₀₀, —S(O)₂R₂₀₀ wherein    R₂₀₀ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;-   wherein each R₁₀₀ and R₁₀₁ is hydrogen, deuterium, halogen, alkyl,    substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl, —OR₂₀₀, —SR₂₀₀,    —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂, —NC(O)R₂₀₀, —S(O)₂R₂₀₀ wherein R₂₀₀ is    hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;    alternatively two of R₁₀₀ and R₁₀₁ groups together with the atoms to    which they are attached and any intervening atoms may form an    additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;-   Cy₃ is absent, an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   Cy₅ is a spiro attached C₃-C₆ carbocycle, preferably cyclopropyl or    cyclobutyl;-   A₂ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    —S(O)₂R₁₀₀, —S(O)R₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁);-   A₃ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    S(O)₂R₁₀₀, S(O)R₁₀₀, S(O)₂N(R₁₀₀)(R₁₀₁);-   R₂ is independently selected from hydrogen, deuterium, halogen,    alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, or substituted heteroaryl —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;    alternatively two R₂ together with the atoms to which they are    attached may form an optionally substituted 3, 4, 5, 6 or 7 membered    ring, preferably a cycloalkyl, substituted cycloalkyl, heterocycle,    substituted heterocycle, aryl, substituted aryl, heteroaryl or    substituted heteroaryl group; and,-   each R₃ and R₄ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃.

In one embodiment, the invention relates to a compound of Formula V,having the formula:

-   or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention relates to a compound of Formula VI:

-   or a pharmaceutically acceptable salt, ester or prodrug thereof-   wherein    represents a single or double bond;-   wherein W₁ is CH, CH₂, CR₁₀₀, C(O), O, S, SO, or SO₂;-   m is 0, 1, 2, 3 or 4;-   Cy₁ is absent, an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   Cy₂ is an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   A₁ is absent, —[C(R₁₀₀)(R₁₀₁)]_(n)—, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —S(O)₂N(R₁₀₀)—, —S(O)₂, carbocycle, substituted    carbocycle, heterocycle, substituted heterocycle, aromatic,    substituted aromatic, heteroaromatic or substituted heteroaromatic;    wherein n is 0, 1, 2, 3, 4, 5, 6 or 7;-   wherein each R₁₀₀ and R₁₀₁ is hydrogen, deuterium, halogen, alkyl,    substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl, —OR₂₀₀, —SR₂₀₀,    —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂, —NC(O)R₂₀₀, —S(O)₂R₂₀₀ wherein R₂₀₀ is    hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;    alternatively two of R₁₀₀ and R₁₀₁ groups together with the atoms to    which they are attached and any intervening atoms may form an    additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;-   A₂ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    —S(O)₂R₁₀₀, —S(O)R₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁),-   A₃ is absent or —[C(R₁₀₀)(R₁₀₁)]r-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    S(O)₂R₁₀₀, S(O)R₁₀₀, S(O)₂N(R₁₀₀)(R₁₀₁);-   A₄ is —[C(R₂₅)(R₂₆)]r-, —[C(R₂₅)(R₂₆)]r-C═C—[C(R₂₇)(R₂₈)]p, or    —[C(R₂₅)(R₂₆)]r—C≡C—[C(R₂₇)(R₂₈)]p;-   wherein each R₂₅, R₂₆, R₂₇ and R₂₈ is hydrogen, deuterium, halogen,    alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl,    alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,    aliphatic, substituted aliphatic, aryl, substituted aryl, —OR₁₀₀,    —SR₁₀₀, —NR₁₀₀R₁₀₁, —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁,    —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀, —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁,    —CF₃, —CN, —NO₂, and —N₃; alternatively two of R₂₅, R₂₆, R₂₇ and R₂₈    groups together with the atoms to which they are attached and any    intervening atoms may form an additional optionally substituted, 3,    4, 5, 6 or 7 membered ring; preferably a cyclopropyl group;-   p is 0, 1, 2, 3, 4, 5, 6, or 7;-   r is 1, 2, 3, 4, 5, 6, or 7;-   R₂ is independently selected from hydrogen, deuterium, halogen,    alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, or substituted heteroaryl —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;    alternatively two R₂ together with the atoms to which they are    attached may form an optionally substituted 3, 4, 5, 6 or 7 membered    ring, preferably a cycloalkyl, substituted cycloalkyl, heterocycle,    substituted heterocycle, aryl, substituted aryl, heteroaryl or    substituted heteroaryl group; and,-   each R₃ and R₄ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃.

In one embodiment, the invention relates to a compound of Formula VII:

-   or a pharmaceutically acceptable salt, ester or prodrug thereof;-   wherein    represents a single or double bond;-   wherein W₁ is CH, CH₂, CR₁₀₀, C(O), O, S, SO, or SO₂;-   m is 0, 1, 2, 3 or 4;-   s is 1, 2, 3 or 4;-   Cy₁ is absent, an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   Cy₂ is an aryl, substituted aryl, carbocycle, substituted    carbocycle, heterocyclyl, substituted heterocyclyl, heteroaryl, or    substituted heteroaryl group having one, two or three rings;-   A₁ is absent, —[C(R₁₀₀)(R₁₀₁)]_(n)—, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —S(O)₂N(R₁₀₀)—, —S(O)₂—, carbocycle, substituted    carbocycle, heterocycle, substituted heterocycle, aromatic,    substituted aromatic, heteroaromatic or substituted heteroaromatic;    wherein n is 0, 1, 2, 3, 4, 5, 6 or 7;-   wherein each R₁₀₀ and R₁₀₁ is hydrogen, deuterium, halogen, alkyl,    substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl, —OR₂₀₀, —SR₂₀₀,    —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂, —NC(O)R₂₀₀, —S(O)₂R₂₀₀ wherein R₂₀₀ is    hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;    alternatively two of R₁₀₀ and R₁₀₁ groups together with the atoms to    which they are attached and any intervening atoms may form an    additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;-   A₂ is absent or —[C(R₁₀₀)(R₁₀₁)]n-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    —S(O)₂R₁₀₀, —S(O)R₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁);-   A₃ is absent or —[C(R₁₀₀)(R₁₀₁)]r-, —C(O)—, —C(S)—, —S(O)—,    —C(O)N(R₁₀₀)—, —C(O)N(R₁₀₀)(R₁₀₁), N(R₁₀₀)(R₁₀₁), —S(O)₂—,    S(O)₂R₁₀₀, S(O)R₁₀₀, S(O)₂N(R₁₀₀)(R₁₀₁);-   A₄ is absent, —[C(R₂₅)(R₂₆)]r-, —[C(R₂₅)(R₂₆)]r-C═C—[C(R₂₇)(R₂₈)]p,    or —[C(R₂₅)(R₂₆)]r-C≡C—[C(R₂₇)(R₂₈)]p;-   wherein each R₂₅, R₂₆, R₂₇ and R₂₈ is hydrogen, deuterium, halogen,    alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl,    alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,    aliphatic, substituted aliphatic, aryl, substituted aryl, —OR₁₀₀,    —SR₁₀₀, —NR₁₀₀R₁₀₁, —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁,    —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀, —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁,    —CF₃, —CN, —NO₂, and —N₃; alternatively two of R₂₅, R₂₆, R₂₇ and R₂₈    groups together with the atoms to which they are attached and any    intervening atoms may form an additional optionally substituted, 3,    4, 5, 6 or 7 membered ring; preferably a cyclopropyl group;-   p is 0, 1, 2, 3, 4, 5, 6, or 7;-   r is 1, 2, 3, 4, 5, 6, or 7;-   R₂ is independently selected from hydrogen, deuterium, halogen,    alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, or substituted heteroaryl —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃;    alternatively two R₂ together with the atoms to which they are    attached may form an optionally substituted 3, 4, 5, 6 or 7 membered    ring, preferably a cycloalkyl, substituted cycloalkyl, heterocycle,    substituted heterocycle, aryl, substituted aryl, heteroaryl or    substituted heteroaryl group; and,-   each R₃ and R₄ is independently selected from hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,    heteroaryl, substituted heteroaryl, or —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁,    —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀,    —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂, —N₃; and,-   each R₁₄₀ is independently selected from halogen, —OR₁₀₀, —SR₁₀₀,    —NR₁₀₀R₁₀₁, —C(C)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁,    —S(O)₂R₁₀₀, —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁, —CF₃, —CN, —NO₂,    —N₃.

In one embodiment, the invention relates to a compound of Formula V-VIIwherein Cy2 is selected from:

-   wherein q is 0, 1, 2, 3, 4 or 5;-   each R₁₀₂ is independently hydrogen, deuterium, halogen, alkyl,    substituted alkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, aliphatic, substituted aliphatic, carbocycle,    substituted carbocycle, aryl, substituted aryl, —OR₁₀₀, —SR₁₀₀,    —NR₁₀₀R₁₀₁, —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁,    —S(O)₂R₁₀₀, —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁—CF₃, —CN, —NO₂,    —N₃; alternatively two of R₁₀₂ groups together with the atoms to    which they are attached and any intervening atoms may form an    additional optionally substituted 3, 4, 5, 6 or 7 membered ring; and-   R₁₀₅ is hydrogen, deuterium, alkyl, substituted alkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl.

In one embodiment, the invention relates to a compound of Formula V-VIIwherein Cy1 is selected from:

-   wherein q is 0, 1, 2, 3, 4 or 5; each R₁₀₂ is hydrogen, deuterium,    halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,    alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,    carbocycle, substituted carbocycle, aryl, substituted aryl, —OR₁₀₀,    —SR₁₀₀, —NR₁₀₀R₁₀₁, —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁,    —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀, —S(O)R₁₀₀, —SR₁₀₀,    —S(O)₂N(R₁₀₀)R₁₀₁—CF₃, —CN, —NO₂, —N₃; alternatively two of R₁₀₂    groups together with the atoms to which they are attached and any    intervening atoms may form an additional optionally substituted 3,    4, 5, 6 or 7 membered ring; and,-   R₁₀₃ is hydrogen, deuterium, alkyl, substituted alkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,    substituted aliphatic, aryl and substituted aryl.

In one embodiment, the invention relates to a compound of Formula Vwherein Cy3 is selected from:

-   each R₃₀, R₃₁, R₃₂ and R₃₃ is independently selected from hydrogen,    deuterium, halogen, alkyl, substituted alkyl, alkenyl, substituted    alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted    aliphatic, carbocycle, substituted carbocycle, aryl, substituted    aryl, —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁, —C(O)R₁₀₀, —C(O)OR₁₀₀,    —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀, —S(O)R₁₀₀, —SR₁₀₀,    —S(O)₂N(R₁₀₀)R₁₀₁—CF₃, —CN, —NO₂, —N₃; alternatively two of R₃₀,    R₃₁, R₃₂ or R₃₃ groups together with the atoms to which they are    attached and any intervening atoms may form an additional optionally    substituted 3, 4, 5, 6 or 7 membered ring; and,-   q is 0, 1, 2, 3, 4 or 5.

In a more preferred embodiment, a compound of formula I is selected fromTable A:

TABLE A Structure

In a preferred embodiment, the invention relates to a compound selectedfrom Table A2 or a pharmaceutically acceptable salt thereof:

TABLE A2

The compounds of this invention may be prepared by methods known in theart. Exemplary synthetic routes to prepare compounds of this inventionare illustrated below:

Compounds of the invention are useful as modulators of CFTR and treatingdiseases or disorders mediated by CFTR such as for the treatment ofdisease, disorders or conditions such as cystic fibrosis, hereditaryemphysema, hereditary hemochromatosis, coagulation-fibrinolysisdeficiencies, type 1 hereditary angioedema, lipid processingdeficiencies, such as familial hypercholesterolemia, type 1chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, suchas I-cell diseasepseudo-Hurler, mucopolysaccharidoses, SandhofTay-Sachs,Crigler-Najjar type II, polyendocrinopathyhyperinsulemia, diabetesmellitus, Laron dwarfism, myeloperoxidase deficiency, primaryhypoparathyroidism, melanoma, glycanosis CDG type 1, congenitalhyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia,ACT deficiency, diabetes insipidus (DI), neurophyseal DI, neprogenic DI,Charcot-Marie tooth syndrome, Perlizaeus-Merzbacher disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, progressive supranuclear palsy,Pick's disease, several polyglutamine neurological disorders such asHuntington's disease, Spinocerebullar ataxia type I, Spinal and bulbarmuscular atrophy, Dentororubal pallidoluysian, and Myotic dystrophy, aswell as, spongiform encephalopathies such as HereditaryCreutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker disease,secretory diarrhea, polycystic kidney disease, chronic obstructivepulmonary disease (COPD), dry eye disease, or Sjogren's Syndrome.

The compounds of the invention may be administered in combination withantibiotics, anti-inflammatory medicines, bronchoditators, ormucus-thinning medicines. In particular antibiotics for the treatment ofbacteria mucoid Pseudomonas may be used in combination with compounds ofthe invention. Inhaled antibiotics such as tobramycin, colistin, andaztreonam can be used in combination with treatment with compounds ofthe invention. Anti-inflammatory medicines may also be used incombination with compounds of the invention to treat CFTR relateddiseases. Bronchodilators can be used in combination with compounds ofthe invention to treat CFTR related diseases.

In one embodiment, the invention relates to combination therapycomprising compounds of the invention and other pharmaceutical agentsuseful for the treatment of CF. In a preferred embodiment, theaminoglycoside gentamicin can be used. In a preferred embodiment,ataluren, ivacaftor (Kalydeco) VX-809 may be used in combination withcompounds of the invention.

In one embodiment, the invention relates to pharmaceutical compositionscomprising compounds of the invention and pharmaceutically acceptablecarriers. The compositions may include compounds of the invention, andoptionally a pharmaceutically acceptable carrier, adjuvant or vehicle.In certain embodiments, these compositions optionally further compriseone or more additional therapeutic agents useful tbr the treatment ofCFTR mediated diseases or disorders.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid, gel or liquidfiller, diluent, encapsulating material or formulation auxiliary of anytype. Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;cyclodextrins such as alpha-(α), beta- (β) and gamma- (γ) cyclodextrins;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. In a preferredembodiment, administration is parenteral administration by injection.

The pharmaceutical compositions of this invention may contain anyconventional non-toxic pharmaceutically-acceptable carriers, adjuvantsor vehicles. In some cases, the pH of the formulation may be adjustedwith pharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form. The termparenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intraarticular, intraarterial,intrasynovial, intrasternal, intrathecal, intralesional and intracranialinjection or infusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, EtOAc, benzylalcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol,dimethylformamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof. Besides inert diluents, the oral compositions can alsoinclude adjuvants such as wetting agents, emulsifying and suspendingagents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesuspension or emulsion, such as INTRALIPID®, LIPOSYN® or OMEGAVEN®, orsolution, in a nontoxic parenterally acceptable diluent or solvent, forexample, as a solution in 1, 3-butanediol. INTRALIPID® is an intravenousfat emulsion containing 10-30% soybean oil, 1-10% egg yolkphospholipids, 1-10% glycerin and water. LIPOSYN® is also an intravenousfat emulsion containing 2-15% safflower oil, 2-15% soybean oil, 0.5-5%egg phosphatides 1-10% glycerin and water. OMEGAVEN® is an emulsion forinfusion containing about 5-25% fish oil, 0.5-10% egg phosphatides,1-10% glycerin and water. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution, USP and isotonicsodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid are used inthe preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid; b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate; h) absorbents such as kaolinand bentonite clay; and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics is knownin the art (see, for example U.S. Pat. No. 5,767,068 to VanDevanter etal., U.S. Pat. No. 5,508,269 to Smith et al., and WO 98/43650 byMontgomery).

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aliphatic group” or “aliphatic” refers to a non-aromaticmoiety that may be saturated (e.g. single bond) or contain one or moreunits of unsaturation, e.g., double and/or triple bonds. An aliphaticgroup may be straight chained, branched or cyclic, contain carbon,hydrogen or, optionally, one or more heteroatoms and may be substitutedor unsubstituted. In addition to aliphatic hydrocarbon groups, aliphaticgroups include, for example, polyalkoxyalkyls, such as polyalkyleneglycols, polyamines, and polyimines, for example. Such aliphatic groupsmay be further substituted. It is understood that aliphatic groups mayinclude alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, and substituted or unsubstituted cycloalkyl groupsas described herein.

The term “acyl” refers to a carbonyl substituted with hydrogen, alkyl,partially saturated or fully saturated cycloalkyl, partially saturatedor fully saturated heterocycle, aryl, or heteroaryl. For example, acylincludes groups such as (C₁-C₆)alkanoyl (e.g., formyl, acetyl,propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl,tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl(e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitions.When indicated as being “optionally substituted”, the acyl group may beunsubstituted or optionally substituted with one or more substituents(typically, one to three substituents) independently selected from thegroup of substituents listed below in the definition for “substituted”or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion ofthe acyl group may be substituted as described above in the preferredand more preferred list of substituents, respectively.

The term “alkyl” is intended to include both branched and straightchain, substituted or unsubstituted saturated aliphatic hydrocarbonradicalsgroups having the specified number of carbons. Preferred alkylgroups comprise about 1 to about 24 carbon atoms (“C₁-C₂₄”). Otherpreferred alkyl groups comprise at about 1 to about 8 carbon atoms(“C₁-C₈”) such as about 1 to about 6 carbon atoms (“C₁-C₆”), or such asabout 1 to about 3 carbon atoms (“C₁-C₃”). Examples of C₁-C₆ alkylradicals include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, n-pentyl, neopentyl and n-hexylradicals.

The term “alkenyl” refers to linear or branched radicals having at leastone carbon-carbon double bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”). Other preferredalkenyl radicals are “lower alkenyl” radicals having two to about tencarbon atoms (“C₂-C₁₀”) such as ethenyl, allyl, propenyl, butenyl and4-methylbutenyl. Preferred lower alkenyl radicals include 2 to about 6carbon atoms (“C₂-C₆”). The terms “alkenyl”, and “lower alkenyl”,embrace radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations.

The term “alkynyl” refers to linear or branched radicals having at leastone carbon-carbon triple bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”). Other preferredalkynyl radicals are “lower alkynyl” radicals having two to about tencarbon atoms such as propargyl, 1-propynyl, 2-propynyl, 1-butyne,2-butynyl and 1-pentynyl. Preferred lower alkynyl radicals include 2 toabout 6 carbon atoms (“C₂-C₆”).

The term “cycloalkyl” refers to saturated carbocyclic radicals havingthree to about twelve carbon atoms (“C₃-C₁₂”). The term “cycloalkyl”embraces saturated carbocyclic radicals having three to about twelvecarbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “cycloalkenyl” refers to partially unsaturated carbocyclicradicals having three to twelve carbon atoms. Cycloalkenyl radicals thatare partially unsaturated carbocyclic radicals that contain two doublebonds (that may or may not be conjugated) can be called“cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “alkylene,” as used herein, refers to a divalent group derivedfrom a straight chain or branched saturated hydrocarbon chain having thespecified number of carbons atoms. Examples of alkylene groups include,but are not limited to, ethylene, propylene, butylene,3-methyl-pentylene, and 5-ethyl-hexylene.

The term “alkenylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbondouble bond. Alkenylene groups include, but are not limited to, forexample, ethenylene, 2-propenylene, 2-butenylene,1-methyl-2-buten-1-ylene, and the like.

The term “alkynylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbontriple bond. Representative alkynylene groups include, but are notlimited to, for example, propynylene, 1-butynylene,2-methyl-3-hexynylene, and the like.

The term “alkoxy” refers to linear or branched oxy-containing radicalseach having alkyl portions of one to about twenty-four carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkoxyradicals are “lower alkoxy” radicals having one to about ten carbonatoms and more preferably having one to about eight carbon atoms.Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy.

The term “alkoxyalkyl” refers to alkyl radicals having one or morealkoxy radicals attached to the alkyl radical, that is, to formmonoalkoxyalkyl and dialkoxyalkyl radicals.

The term “aryl”, alone or in combination, means an aromatic systemcontaining one, two or three rings wherein such rings may be attachedtogether in a pendent manner or may be fused. The term “aryl” embracesaromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanefuranyl, quinazolinyl, pyridyl and biphenyl.

The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo”refer to saturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, which can also be called“heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclyl radicals include saturated 3 to6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partiallyunsaturated heterocyclyl radicals include dihydrothiophene,dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicalsmay include a pentavalent nitrogen, such as in tetrazolium andpyridinium radicals. The term “heterocycle” also embraces radicals whereheterocyclyl radicals are fused with aryl or cycloalkyl radicals.Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like.

The term “heteroaryl” refers to unsaturated aromatic heterocyclylradicals. Examples of heteroaryl radicals include unsaturated 3 to 6membered heteromonocyclic group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “heterocycloalkyl” refers to heterocyclo-substituted alkylradicals. More preferred heterocycloalkyl radicals are “lowerheterocycloalkyl” radicals having one to six carbon atoms in theheterocyclo radical.

The term “alkylthio” refers to radicals containing a linear or branchedalkyl radical, of one to about ten carbon atoms attached to a divalentsulfur atom. Preferred alkylthio radicals have alkyl radicals of one toabout twenty-four carbon atoms or, preferably, one to about twelvecarbon atoms. More preferred alkylthio radicals have alkyl radicalswhich are “lower alkylthio” radicals having one to about ten carbonatoms. Most preferred are alkylthio radicals having lower alkyl radicalsof one to about eight carbon atoms. Examples of such lower alkylthioradicals include methylthio, ethylthio, propylthio, butylthio andhexylthio.

The terms “aralkyl” or “arylalkyl” refer to aryl-substituted alkylradicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl,and diphenylethyl.

The term “aryloxy” refers to aryl radicals attached through an oxygenatom to other radicals.

The terms “aralkoxy” or “arylalkoxy” refer to aralkyl radicals attachedthrough an oxygen atom to other radicals.

The term “aminoalkyl” refers to alkyl radicals substituted with aminoradicals. Preferred aminoalkyl radicals have alkyl radicals having aboutone to about twenty-four carbon atoms or, preferably, one to abouttwelve carbon atoms. More preferred aminoalkyl radicals are “loweraminoalkyl” that have alkyl radicals having one to about ten carbonatoms. Most preferred are aminoalkyl radicals having lower alkylradicals having one to eight carbon atoms. Examples of such radicalsinclude aminomethyl, aminoethyl, and the like.

The term “alkylamino” denotes amino groups which are substituted withone or two alkyl radicals. Preferred alkylamino radicals have alkylradicals having about one to about twenty carbon atoms or, preferably,one to about twelve carbon atoms. More preferred alkylamino radicals are“lower alkylamino” that have alkyl radicals having one to about tencarbon atoms. Most preferred are alkylamino radicals having lower alkylradicals having one to about eight carbon atoms. Suitable loweralkylamino may be monosubstituted N-alkylamino or disubstitutedN,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino,trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted.

For simplicity, chemical moieties that are defined and referred tothroughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.)or multivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g. CH₃—CH₂—), or in other instances,a bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” Similarly, incircumstances in which divalent moieties are required and are stated asbeing “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”,or “cycloalkyl”, those skilled in the art will understand that the terms“alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”,“heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or“cycloalkyl” refer to the corresponding divalent moiety.

The terms “halogen” or “halo” as used herein, refers to an atom selectedfrom fluorine, chlorine, bromine and iodine.

The terms “compound” “drug,” and “prodrug” as used herein all includepharmaceutically acceptable salts, co-crystals, solvates, hydrates,polymorphs, enantiomers, diastereoisomers, racemates and the like of thecompounds, drugs and prodrugs having the formulas as set forth herein.

Substituents indicated as attached through variable points ofattachments can be attached to any available position on the ringstructure.

As used herein, the term “effective amount of the subject compounds,”with respect to the subject method of treatment, refers to an amount ofthe subject compound which, when delivered as part of desired doseregimen, brings about management of the disease or disorder toclinically acceptable standards.

“Treatment” or “treating” refers to an approach for obtaining beneficialor desired clinical results in a patient. For purposes of thisinvention, beneficial or desired clinical results include, but are notlimited to, one or more of the following: alleviation of symptoms,diminishment of extent of a disease, stabilization (i.e., not worsening)of a state of disease, preventing spread (i.e., metastasis) of disease,preventing occurrence or recurrence of disease, delay or slowing ofdisease progression, amelioration of the disease state, and remission(whether partial or total).

EXAMPLES Example 1 Synthesis ofN-ethyl-N-(4-ethylphenyl)-2-(1-oxo-4-phenylphthalazin-2(1H)-yl)acetamide

2-bromo-N-ethyl-N-(4-ethylphenyl)acetamide

4-Ethylaniline (5.13 mL, 41.3 mmol) in THF (44 mL) was cooled to 0° C.and treated with a solution of acetaldehyde (2.55 mL, 45.4 mmol) andH₂SO₄ (3.09 mL, 12.38 mmol) in THF (117 mL). The resulting white slurrywas stirred for 10 min, then treated with NaBH₄ (1.03 g, 27.2 mmol).After 4 hrs, additional NaBH₄ (0.390 g, 10.32 mmol) was added andstirring maintained overnight. The reaction was quenched with sat'dNH₄Cl and extracted with Et₂O. The organic phase was washed with brine,dried over MgSO₄ and evaporated to dryness. The crude product waspurified by silica gel chromatography (10-20% EtOAc/hexane) to yield 3.0g (48%) of N,4-diethylaniline. A solution of N,4-diethylaniline (0.5 g,2.95 mmol), DMAP (0.018 g, 0.147 mmol), and 2-bromoacetic acid (0.975 g,7.02 mmol) in DCM (29.5 mL) was treated with EDC.HCl (1.35 g, 7.08 mmol)and stirred at rt for 12 hrs. The reaction was diluted with DCM, washedwith brine and 2N NaOH, dried over MgSO₄ and evaporated to dryness. Thecrude product was purified by silica gel chromatography (10-20%EtOAc/pet ether) to yield 2-bromo-N-ethyl-N-(4-ethylphenyl)acetamide(650 mg).

4-oxo-3,4-dihydrophthalazin-1-yl 4-methylbenzenesulfonate

A solution of 2,3-dihydrophthalazine-1,4-dione (10 g, 61.7 mmol) inpyridine (190 mL) under N₂ was treated with tosyl chloride (11.76 g,61.7 mmol), heated to reflux for 3 hrs, and then stirred at rtovernight. The reaction was concentrated and dissolved in 1:1 EtOAc andsat'd NaHCO₃. The precipitate was filtered, washed with water, EtOAc,and sat'd NaHCO₃, and then dried overnight to yield4-oxo-3,4-dihydrophthalazin-1-yl 4-methylbenzenesulfonate (12.9 g, 66%)(MS: ESI+ve, 317 [M+H]).

3-(2-(ethyl(4-ethylphenyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazin-1-yl4-methylbenzenesulfonate

NaH (60%) (0.306 g, 7.64 mmol) was suspended in DMF (66 mL) and treatedwith 4-oxo-3,4-dihydrophthalazin-1-yl 4-methylbenzenesulfonate (2.10 g,6.65 mmol) in portions over ˜1 min. When the bubbling had subsided,2-bromo-N-ethyl-N-(4-ethylphenyl)acetamide (1.5 g, 6.65 mmol) and NaI(0.50 g, 3.32 mmol) were added. After stirring overnight, the reactionwas quenched by addition of ice, then diluted with DCM. The aq. layerwas extracted with DCM (2×), and the combined organic layers were washed4×5% LiCl (aq) and brine, dried with MgSO₄, and evaporated onto silicagel. The material was chromatographed (20% EtOAc/pet ether) to yield3-(2-(ethyl(4-ethylphenyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazin-1-yl4-methylbenzenesulfonate (1.62 g, 48%), (MS: ESI+ve, 506 [M+H]).

Example 1N-ethyl-N-(4-ethylphenyl)-2-(1-oxo-4-phenylphthalazin-2(1H)-yl)acetamide

A microwave vial containing3-(2-(ethyl(4-ethylphenyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazin-1-yl4-methylbenzenesulfonate (50 mg, 0.099 mmol), phenylboronic acid (24.12mg, 0.198 mmol), Na₂CO₃ (26.2 mg, 0.247 mmol), andbis(triphenylphosphine)palladium (II) chloride (4.86 mg, 6.92 μmol) wasflushed with N₂, then treated with THF (1.5 mL) and water (0.5 mL). Themixture was heated in the microwave at 155° C. for 45 min. It wasfiltered and the product extracted 3× EtOAc. The combined organic layerswere washed with water and brine, dried over MgSO₄, and evaporated todryness. The resulting material was purified by reverse phase HPLC todeliverN-ethyl-N-(4-ethylphenyl)-2-(1-oxo-4-phenylphthalazin-2(1H)-yl)acetamide(8.8 mg), (MS: ESI+ve, 412 [M+H]).

Representative compounds of the invention were prepared in a similarmanner to example 1 (scheme 1) using the appropriate alkylating agentand commercially available boronic acid or boronic ester.

Example No. Structure IUPAC Name LCMS m/z 2.

N-ethyl-N-(4-ethylphenyl)-2-(4- (4-hydroxyphenyl)-1-oxophthalazin-2(1H)- yl)acetamide: 428 [M + H] 3.

N-ethyl-N-(4-ethylphenyl)-2-(1- oxo-4-(pyridin-3-yl)phthalazin-2(1H)-yl)acetamide 413 [M + H] 4.

N-ethyl-N-(4-ethylphenyl)-2-(1- oxo-4-(pyridin-4-yl)phthalazin-2(1H)-yl)acetamide 413 [M + H] 5.

N-ethyl-N-(4-ethylphenyl)-2-(1- oxo-4-(quinolin-5-yl)phthalazin-2(1H)-yl)acetamide 463 [M + H] 6.

N-ethyl-N-(4-ethylphenyl)-2-(4- (isoquinolin-5-yl)-1-oxophthalazin-2(1H)- yl)acetamide 463 [M + H] 7.

N-ethyl-N-(4-ethylphenyl)-2-(1- oxo-4-(pyrimidin-5-yl)phthalazin-2(1H)-yl)acetamide 414 [M + H] 8.

2-(4-(3-aminophenyl)-1- oxophthalazin-2(1H)-yl)-N-ethyl-N-(4-ethylphenyl)acetamide 427 [M + H] 9.

N-ethyl-N-(4-ethylphenyl)-2-(4- (3-hydroxyphenyl)-1-oxophthalazin-2(1H)- yl)acetamide 428 [M + H] 10.

2-(4-(benzo[d][1,3]dioxol-4-yl)- 1-oxophthalazin-2(1H)-yl)-N-ethyl-N-(4- ethylphenyl)acetamide 456 [M + H] 11.

3-(3-(2-(ethyl(4- ethylphenyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazin-1- yl)benzamide 455 [M + H] 12.

4-(3-(2-(ethyl(4- ethylphenyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazin-1- yl)benzamide 455 [M + H] 13.

N-ethyl-N-(4-ethylphenyl)-2-(1- oxo-4-(4- sulfamoylphenyl)phthalazin-2(1H)-yl)acetamide 491 [M + H] 14.

4-(3-(2-(ethyl(4- ethylphenyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazin-1- yl)benzoic acid 456 [M + H] 15.

methyl 4-(3-(2-(ethyl(4- ethylphenyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazin-1- yl)benzoate 470 [M + H] 16.

N-ethyl-N-(4-ethylphenyl)-2-(4- (4-(methylsulfonyl)phenyl)-1-oxophthalazin-2(1H)- yl)acetamide 490 [M + H] 17.

2-(4-(3-cyanophenyl)-1- oxophthalazin-2(1H)-yl)-N-ethyl-N-(4-ethylphenyl)acetamide 437 [M + H] 18.

N-(2,2-difluorobenzo[d][1, 3]dioxol-5-yl)-N-ethyl-2-(1-oxo- 4-(4-suflamoyl0phenyl)phthalazin- 2(1H)-yl)acetamide 543 [M + H] 19.

4-(3-(2-((2,2-difluorobenzo[d][1, 3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-4-oxo-3,4- dihydrophthalazin-1- yl)benzamide 507 [M + H] 20.

4-(3-(2-((2,2-difluorobenzo[d][1, 3]dioxol-5-yl)(ethylamino)-2-oxoethyl)-4-oxo-3,4- dihydrophthalazin-1-yl)benzoic acid 508 [M + H] 21.

2-(4-(3-cyanophenyl)-1- oxophthalazin-2(1H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)-N-ethylacetamide 489 [M + H] 22.

2-(4-(3-chlorophenyl)-1- oxophthalazin-2(1H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)-N-ethylacetamide 23.

N-(2,2-difluorobenzo[d][1, 3]dioxol-5-yl)-N-ethyl-2-(4-(3-fluorophenyl)-1-oxophthalazin- 2(1H)-yl)acetamide 24.

N-(2,2-difluorobenzo[d][1, 3]dioxol-5-yl)-N-ethyl-2-(1-oxo-4-(pyridin-3-yl)phthalazin-2(1H)- yl)acetamide

N-ethyl-2,2-difluorobenzo[d][1,3]dioxol-5-amine

To a solution of 2,2-difluoro-5-aminobenzo[d][1,3]dioxole (7.45 g, 43.0mmol) in DMF (60 mL) was added K₂CO₃ (17.8 g, 129 mmol), and thereaction mixture was stirred at rt for 1 hr. The reaction was cooled to0° C. and EtI (3.52 mL, 43.0 mmol) added dropwise. After stirring at rtovernight, the reaction mixture was diluted with water (500 mL) and theproduct extracted with EtOAc (3×100 mL). The combined organics werewashed with brine (200 mL), dried over Na₂SO₄, and concentrated. Thecrude product was purified by chromatography (0-10% EtOAc/hexane) toyield N-ethyl-2,2-difluorobenzo[d][1,3]dioxol-5-amine (5.98 g), (MS:ESI+ve, 202 [M+H]).

2-Bromo-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethylacetamide

A solution of N-ethyl-2,2-difluorobenzo[d][1,3]dioxol-5-amine (8.0 g,3.9 mmol) in DCM (100 mL) was treated with 2-bromoacetic acid (13.2 g,9.4 mmol), EDC.HCL (14.8 g, 93.6 mmol), and DMAP (238 mg, 19.5 mmol),then stirred at rt overnight. The reaction mixture was diluted withwater (500 mL) and the product extracted with DCM (3×100 mL). Thecombined organics were washed with brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by chromatography (0-7%EtOAc/hexane) to yield2-bromo-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethylacetamide (11.0g), (MS: ESI+ve, 322 [M+H]). ¹H NMR: (400 MHz, DMSO) δ: 1.03-1.00 (t,J=14.4, 3H), 3.68-3.63 (m, 2H), 4.03 (s, 2H) 7.26-7.23 (d, J=8.4, 1H),7.53-7.50 (d, J=8.4, 1H), 7.57 (s, 1H).

3-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazin-1-yl4-methylbenzenesulfonate

A 0° C. solution of 4-oxo-3,4-dihydrophthalazin-1-yl4-methylbenzenesulfonate (0.37 g, 1.2 mmol) in DMF (6 mL) was treatedwith NaHMDS (2M in THF) (0.65 mL, 1.30 mmol). After stirring for 20 min,a solution of2-bromo-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethylacetamide (0.458g, 1.423 mmol) in DMF (1.0 mL) was added and the mixture stirredovernight at rt. The reaction was quenched with 5% LiCl (aq) andextracted with EtOAc. The combined organics were dried over MgSO₄ andconcentrated. The crude product was purified by chromatography (10-100%EtOAc/pet ether) to yield3-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazin-1-yl4-methylbenzenesulfonate (479 mg), (MS: ESI+ve, 558[M+H]).

3-(pyridin-3-ylmethylene)isobenzofuran-1(3H)-one

A mixture of 3-(carboxymethyl)pyridin-1-ium chloride (13 g, 75 mmol),isobenzofuran-1,3-dione (11.09 g, 75 mmol), and NaOAc (0.246 g, 3.00mmol) was placed into a round bottom flask and warmed to 190° C. for 30minutes. The mixture was extracted with DCM and washed with NaHCO₃ (aq).The organic phase was dried over MgSO₄ and evaporated to give3-(pyridin-3-ylmethylene)isobenzofuran-1(3H)-one (8.5 g).

4-(pyridin-3-ylmethyl)phthalazin-1(2H)-one

Two microwave vials containing3-(pyridin-3-ylmethylene)isobenzofuran-1(3H)-one (1.5 g, 6.72 mmol),hydrazine sulfate (0.874 g, 6.72 mmol), water (6.5 mL), EtOH (1.9 mL)and 2M NaOH (1.9 mL) were flushed with N₂, then heated in a microwave to180° C. for 15 min. The resulting mixtures were cooled to rt and placedin the freezer. The solids were filtered, washed with water, and driedto yield 4-(pyridin-3-ylmethyl)phthalazin-1(2H)-one (2.36 g), (MS:ESI+ve, 238 [M+H]).

Example 25N-ethyl-N-(4-ethylphenyl)-2-(1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)-yl)acetamide

A 0° C. vial of NaH (60%) (6.49 mg, 0.162 mmol) and DMF (738 μL) wastreated with a solution of 4-(pyridin-3-ylmethyl)phthalazin-1(2H)-one(35 mg, 0.148 mmol) in DMF (369 μL). After 10 min,2-bromo-N-ethyl-N-(4-ethylphenyl)acetamide (39.9 mg, 0.148 mmol) in DMF(369 μL) was added and the reaction stirred at rt overnight. Sat'd NH₄Clwas added and the product extracted with EtOAc. The organic phase waswashed with brine, dried over MgSO₄, and evaporated. The crude productwas purified by chromatography (0-5% MeOH EtOAc) to giveN-ethyl-N-(4-ethylphenyl)-2-(1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)-yl)acetamide(20 mg), (MS: ESI+ve, 427 [M+H])

The following compounds were prepared in a similar manner to example 25(scheme 3).

Example No. Structure IUPAC Name LCMS m/z 26.

N-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-N-ethyl-2-(1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)- yl)acetamide 479 [M + H] 27.

N-(4-methoxyphenyl)-N-methyl-2-(1- oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)-yl)acetamide 415 [M + H]

2-chloro-N-(4-methoxyphenyl)-N-methylacetamide

A solution of DMAP (0.022 g, 0.182 mmol) and 4-methoxy-N-methylaniline(0.5 g, 3.64 mmol) in DCM (36 mL) under N₂ was treated with2-chloroacetic acid (1.20 g, 8.67 mmol) and EDC.HCl (1.67 g, 8.75 mmol),then stirred overnight at rt. The reaction was diluted with DCM, thenwashed with brine and 2 M NaOH. The organic layer was dried over MgSO₄,and evaporated to dryness. The crude product was purified bychromatography (10-20% EtOAc pet ether) to give2-chloro-N-(4-methoxyphenyl)-N-methylacetamide (446 mg).

Preparation of 6-methylisobenzofuran-1(3H)-one and5-methylisobenzofuran-1(3H)-one

A solution of 4-methyl phthalic anhydride (5.0 g, 30.8 mmol) in THF (35mL) at 15° C. was treated with HOAc (3.43 mL, 61.6 mmol) and NaBH₄ (1.13g, 30.8 mmol). Stirring was maintained at 15° C. for 30 min and then atrt for 4 hr. The reaction was concentrated under vacuum. HOAc (15 mL)and Ac₂O (15 mL) were added and the mixture heated at 110° C. for 3 hr.The mixture was concentrated, quenched with sat'd NH₄Cl (500 mL) andthen extracted with EtOAc (2×250 mL). The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated. The crude product waspurified by chromatography (0-15% EtOAc/hexane) to obtain a mixture of6-methylisobenzofuran-1(3H)-one and 5-methylisobenzofuran-1(3H)-one (2.0g), (MS: ESI+ve, 149 [M+H]).

3-hydroxy-6-methyl-2-(pyridin-3-yl)-1H-inden-1-one

The mixture of 6-methylisobenzofuran-1(3H)-one and5-methylisobenzofuran-1(3H)-one (2.0 g, 13.5 mmol) was dissolved inEtOAc (10 mL) and MeOH (20 mL), then treated with 3-pyridinecarboxaldehyde (1.44 g, 13.5 mmol) and NaOMe (2.18 g, 40.0 mmol)portionwise at 0° C. The reaction mixture was stirred for 30 min at 0°C. and then heated to 60° C. for 3 h. The reaction mixture wasconcentrated under vacuum, diluted with water (50 mL), and acidifiedwith acetic acid (10 mL). The resulting precipitate was filtered anddried to obtain 3-hydroxy-6-methyl-2-(pyridin-3-yl)-1-H-inden-1-one(1.54 g), (MS: ESI+ve, 238 [M+H]). ¹H NMR: (400 MHz, DMSO) δ: 2.35 (s,3H), 7.20-7.14 (t, 1H), 7.22 (s, 1H), 7.81-7.77 (d, J=8.8 Hz, 1H),8.22-8.20 (d, J=7.6, 1H), 9.47-9.44 (d, J=11.6 Hz, 1H), 9.73 (s, 1H),14.91 (s, 1H).

7-methyl-4-(pyridin-3-ylmethyl)phthalazin-1(2H)-one and6-methyl-4-(pyridin-3-ylmethyl)phthalazin-1(2H)-one

A solution of 3-hydroxy-6-methyl-2-(pyridin-3-yl)-1-H-inden-1-one (1.2g, 5.0 mmol) in hydrazine hydrate (10 mL) was heated at 110° C.overnight. The reaction mixture was diluted with water (50 mL) and theresulting precipitate filtered and dried to obtain7-methyl-4-(pyridin-3-yl-methyl)-phthalazine-1(2H)-one and6-methyl-4-(pyridin-3-yl-methyl)-phthalazine-1(2H)-one (5.01 g), (MS:ESI+ve, 252 [M+H]) as a 1:1 isomeric mixture. ¹H NMR: (400 MHz, DMSO) δ:2.48 (s, 6H), 4.30-4.32 (d, J=2, 4H), 7.34-7.29 (m, 2H), 7.74-7.66 (m,5H), 7.85 (s, 1H), 7.92-7.89 (d, J=8.4, 1H), 8.16-8.14 (d, J=8, 1H),8.41-8.41 (m, 1H), 8.43-8.42 (m, 2H), 8.60-8.43 (m, 2H), 12.51 (s, 2H).

Examples 28 and 29N-ethyl-N-(4-ethylphenyl)-2-(7-methyl-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)-yl)acetamideandN-ethyl-N-(4-ethylphenyl)-2-(6-methyl-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)-yl)acetamide

A solution of 7-methyl-4-(pyridin-3-yl-methyl)-phthalazine-1(2H)-one and6-methyl-4-(pyridin-3-yl-methyl)-phthalazine-1(2H)-one (0.5 g, 1.9 mmol)in THF (15 mL) was treated with NaH (60%) (0.087 g, 2.1 mmol)portionwise at 0° C. and then for 30 min at 0° C. A solution of2-bromo-N-ethyl-N-(4-ethylphenyl)acetamide (0.537 g, 1.9 mmol) in THF (5mL) was added dropwise and the reaction mixture warmed to rt overnight.The reaction was diluted with sat'd NH₄Cl (25 mL) and extracted withEtOAc (2×50 mL). The organics were washed with brine (50 mL), dried overNa₂SO₄, and concentrated to give crude which was purified by preparativeHPLC to obtain the separable isomers, Example 28:N-ethyl-N-(4-ethylphenyl)-2-(7-methyl-1-oxo-4-(pyridine-3-ylmethyl)-phthalazine-2(1H)-yl)acetamide(0.024 g), (MS: ESI+ve, 441 [M+H]); ¹H NMR: (400 MHz, DMSO) δ: 1.05-1.00(m, 3H), 1.23-1.19 (t, 3H), 2.51-2.48 (m, 3H), 2.69-2.63 (m, 2H),3.68-3.63 (m, 2H), 4.31 (s, 2H), 4.55 (s, 2H), 7.36-7.28 (m, 5H),7.72-7.66 (m, 2H), 7.87-7.85 (d, J=8.4, 1H), 8.03 (s, 1H), 8.15 (s, 1H),8.59-8.40 (m, 1H), 8.60 (s, 1H); Example 29:N-ethyl-N-(4-ethylphenyl)-2-(6-methyl-1-oxo-4-(pyridine-3-ylmethyl)-phthalazine-2(1H)-yl)acetamide(0.034 g), (MS: ESI+ve, 441 [M+H]); ¹H NMR: (400 MHz, DMSO) δ: 1.04-1.00(t, 3H), 1.23-1.19 (t, 3H), 2.50 (s, 3H), 2.69-2.63 (m, 2H), 3.68-3.63(m, 2H), 4.32 (s, 2H), 4.54 (s, 2H), 7.36-7.29 (m, 5H), 7.71-7.66 (m,2H), 7.80 (s, 1H), 8.14-8.12 (d, J=8, 1H), 8.43-8.41 (m, 1H), 8.62-8.61(d, J=1.6, 1H).

Representative compounds of the invention were prepared in a similarmanner to examples 28 and 29 from the corresponding phthalic anhydrideor isobenzofuran-1(3H)-one and the appropriate alkylating agent (scheme4).

Example No. Structure IUPAC Name LCMS m/z 30.

N-ethyl-N-(4-ethylphenyl)-2-(8-methyl-1-oxo-4-(pyridin-3-ylmethyl)phthalazin- 2(1H)-yl)acetamide 441 [M + H] 31.

N-ethyl-N-(4-ethylphenyl)-2-(5-methyl-1-oxo-4-(pyridin-3-ylmethyl)phthalazin- 2(1H)-yl)acetamide 441 [M + H] 32.

2-(6,7-dimethoxy-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)-yl)-N-ethyl-N- (4-ethylphenyl)acetamide 487[M + H] 33.

2-(7-(tert-butyl)-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)-yl)-N-ethyl-N- (4-methylphenyl)acetamide 483[M + H] 34.

2-(6-(tert-butyl)-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)-yl)-N-ethyl-N- (4-methylphenyl)acetamide 483[M + H] 35.

N-ethyl-N-(4-ethylphenyl)-2-(7-methoxy-1-oxo-4-(pyridin-3-ylmethyl)phthalazin- 2(1H)-yl)acetamide 457 [M + H]36.

N-ethyl-N-(4-ethylphenyl)-2-(6-methoxy-1-oxo-4-(pyridin-3-ylmethyl)phthalazin- 2(1H)-yl)acetamide 457 [M + H]37.

N-ethyl-N-(4-ethylphenyl)-2-(8-fluoro-1-oxo-4-(pyridin-3-ylmethyl)phthalazin- 2(1H)-yl)acetamide 445 [M + H] 38.

2-(6,7-dichloro-1-oxo-4-(pyriidn-3-ylmethyl)phthalazin-2(1H)-yl)-N-ethyl-N- (4-methylphenyl)acetamide 495[M + H] 39.

2-(7-chloro-1-oxo-4-(pyridin-3- ylmethyl)phthalazin-2(1H)-yl)-N-ethyl-N-(4-methylphenyl)acetamide 461 [M + H] 40.

2-(6-chloro-1-oxo-4-(pyridin-3- ylmethyl)phthalazin-2(1H)-yl)-N-ethyl-N-(4-ethylphenyl)acetamide 461 [M + H] 41.

N-ethyl-N-(4-ethylphenyl)-2-(4-oxo-1- (pyriidn-3-ylmethyl)pyrido[3,4-d]pyridazin-3(4H)-yl)acetamide 428 [M + H] 42.

N-ethyl-N-(4-ethylphenyl)-2-(1-oxo-4- (pyridin-3-ylmethyl)pyrido[3,4-d]pyridazin-2(1H)-yl)acetamide 428 [M + H] 43.

N-ethyl-N-(4-ethylphenyl)-2-(5-oxo-8- (pyridin-3-ylmethyl)pyrido[2,3-d]pyridazin-6(4H)-yl)acetamide 428 [M + H] 44.

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-(6,7-dimethoxy-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)-yl)-N- ethylacetamide 539 [M + H] 45.

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(7-methyl-1-oxo-4-(pyridin- 3-ylmethyl)phthalazin-2(1H)-yl)acetamide 493 [M + H] 46.

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(6-methyl-1-oxo-4-(pyridin- 3-ylmethyl)phthalazin-2(1H)-yl)acetamide 493 [M + H] 47.

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(8-methyl-1-oxo-4-(pyridin- 3-ylmethyl)phthalazin-2(1H)-yl)acetamide 493 [M + H] 48.

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(5-methyl-1-oxo-4-(pyridin- 3-ylmethyl)phthalazin-2(1H)-yl)acetamide 493 [M + H] 49.

2-(6-(tert-butyl)-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N- ethylacetamide 535 [M + H] 50.

2-(7-(tert-butyl)-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N- ethylacetamide 535 [M + H] 51.

N-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)-N-ethyl-2-(6-methoxy-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)- yl)acetamide 509 [M + H] 52.

N-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)-N-ethyl-2-(7-methoxy-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)- yl)acetamide 509 [M + H] 53.

2-(6-chloro-1-oxo-4-(pyridin-3- ylmethyl)phthalazin-2(1H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N- ethylacetamide 513 [M + H] 54.

2-(7-chloro-1-oxo-4-(pyridin-3- ylmethyl)phthalazin-2(1H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N- ethylacetamide 513 [M + H] 55.

N-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)-N-ethyl-2-(8-methoxy-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)- yl)acetamide 509 [M + H] 56.

N-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)-N-ethyl-2-(5-methoxy-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)- yl)acetamide 509 [M + H] 57.

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(8-methoxy-1-oxo-4-(pyridin- 3-ylmethyl)phthalazin-2(1H)-yl)acetamide 523 [M + H] 58.

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(5-ethoxy-1-oxo-4-(pyridin- 3-ylmethyl)phthalazin-2(1H)-yl)acetamide 523 [M + H] 59.

2-(8-(cyclohexyloxy)-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N- ethylacetamide 577 [M + H] 60.

2-(5-(cyclohexyloxy)-1-oxo-4-(pyridin-3-ylmethyl)phthalazin-2(1H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N- ethylacetamide 577 [M + H] 61.

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(8-(2-methoxyethoxy)-1-oxo-4-(pyridin-3-ylmethyl)phthalazin- 2(1H)-yl)acetamide 553 [M + H] 62.

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(5-(2-methoxyethoxy)-1-oxo-4-(pyridin-3-ylmethyl)phthalazin- 2(1H)-yl)acetamide 553 [M + H]

4-hydroxyisobenzofuran-1(3H)-one

A solution of 3-hydroxy benzoic acid (1.0 g, 7.24 mmol) in 40%formaldehyde (20 mL) was treated with conc. HCl (20 mL) and conc. H₂SO₄(1 mL) at rt, then stirred overnight. The reaction mixture wasconcentrated, treated with sat'd NH₄Cl (50 mL) and extracted with EtOAc(2×25 mL). The organic layer was washed with brine, dried over Na₂SO₄,and concentrated. The crude product was purified by silica gelchromatography (0-25% EtOAc/hexane) to give6-hydroxyisobenzofuran-1(3H)-one (0.850 g), (MS: ESI+ve, 151 [M+H]). ¹HNMR (400 MHz, DMSO) δ: 5.31 (s, 2H), 7.28-7.30 (d, J=7.2, 1H), 7.39-7.43(t, 1H), 7.46-7.48 (dd, J=4.0, 1H), 10.25 (s, 1H).

4-methoxyisobenzofuran-1(3H)-one and 7-methoxyisobenzofuran-1(3H)-one

To a solution of 6-hydroxyisobenzofuran-1(3H)-one (4.0 g, 26.0 mmol) inacetone (40 mL) was added K₂CO₃ (14.7 g, 107 mmol) at rt. The mixturewas stirred under N₂ for 30 min, then dimethyl sulfate (11 mL, 106.6mmol) was added and the reaction mixture stirred overnight at rt. It wasconcentrated, treated with sat'd NH₄Cl (500 mL), and extracted withEtOAc (2×50 mL). The organic layer was washed with brine, dried overNa₂SO₄, and concentrated. The crude product was purified by silica gelchromatography (0-60% EtOAc/hexane) to give a mixture of4-methoxylisobenzofuran-1(3H)-one and 7-methoxylisobenzofuran-1(3H)-one(3.5 g), (MS: ESI+ve, 165 [M+H]).

4-ethoxyisobenzofuran-1(3H)-one

To a solution of 6-hydroxyisobenzofuran-1(3H)-one (4.0 g, 26.0 mmol) inacetone (40 mL) was added K₂CO₃ (14.7 g, 106.6 mmol) at rt. The mixturewas stirred at rt under N₂ for 30 min, then diethylsulfate (14 mL, 106.6mmol) was added and the reaction stirred at rt overnight. It wasconcentrated, treated with sat'd NH₄Cl (500 mL), and extracted withEtOAc (2×50 mL). The organic layer was washed with brine, dried overNa₂SO₄, and concentrated. The crude product was purified by silica gelchromatography (0-60% EtOAc/hexane) to give4-ethoxylisobenzofuran-1(3H)-one (3.5 g), (MS: ESI+ve, 179 [M+H]).

4-(cyclohexyloxy)isobenzofuran-1(3H)-one

To a solution of 6-hydroxyisobenzofuran-1(3H)-one (4.0 g, 26.6 mmol) inDMSO (30 mL) was added K-OtBu (8.9 g, 79.9 mmol) at rt and the mixturestirred for 30 min. Cyclohexyl bromide (20.0 mL, 159.9 mmol) was addedand stirring continued at 110° C. overnight. The reaction mixture wasconcentrated, treated with sat'd NH₄Cl (500 mL), and extracted withEtOAc (2×100 mL). The organic layer was washed with brine, dried overNa₂SO₄, and concentrated. The crude product was purified by silica gelchromatography (0-5% EtOAc/hexane) to give4-(cyclohexyloxy)isobenzofuran-1(3H)-one (2.0 g), (MS: ESI+ve, 233[M+H]).

4-(2-methoxyethoxy)isobenzofuran-1(3H)-one

To a solution of 6-hydroxyisobenzofuran-1(3H)-one (3.0 g, 20.0 mmol) inDMF (50 mL) was added NaH (60%) (1.44 g, 20.0 mmol). The mixture wasstirred for 30 min, then 2-bromo ethyl methyl ether (3.0 g, 20.0 mmol)was added and stirring continued overnight. The reaction mixture wasconcentrated, treated with sat'd NH₄Cl (500 mL), and extracted withEtOAc (2×100 mL). The organic layer was washed with brine, dried overNa₂SO₄, and concentrated. The crude product was purified by silica gelchromatography (0-20% EtOAc/hexane) to give4-(2-methoxyethoxy)isobenzofuran-1(3H)-one (3.2 g), (MS: ESI+ve, 209[M+H]).

4-(3-chlorophenyl)phthalazin-1(2H)-one

A solution of 1-chlorophthalazine-4-one (1.0 g, 5.5 mmol),3-chlorophenyl boronic acid (1.3 g, 8.3 mmol), tricyclohexyphosphine(0.058 g, 0.27 mmol), and K₃PO₄ (2.3 g, 11.0 mmol) in THF (20 mL) andwater (5 mL) was degassed with N₂ for 30 min then treated withtri(dibenzylideneacetone)-dipalladium (0.050 g, 0.05 mmol) and heated atreflux overnight. The reaction mixture was diluted with water (100 mL)and the product extracted with EtOAc (2×100 mL). The organics werewashed with brine, dried over Na₂SO₄, and concentrated to give4-(3-chlorophenyl)phthalazin-1(2H)-one (1.2 g), (MS: ESI+ve, 257.12[M+H]). ¹H NMR: (400 MHz, DMSO) δ: 7.58-7.60 (m, 2H), 7.61-7.64 (m, 2H),7.65-7.67 (m, 1H), 7.90-7.93 (m, 2H), 8.34-8.36 (m, 1H). 12.93 (s, 1H).

Example 632-(4-(3-chlorophenyl)-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide

To a solution of 4-(3-chlorophenyl)phthalazin-1(2H)-one (0.5 g, 1.94mmol) in DMF (20 mL) was added NaH (60%) (0.116 g, 2.91 mmol)portionwise at 0° C. After stirring for 30 min,2-bromo-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (0.55 g, 1.94mmol) in DMF (2 mL) was added dropwise and the reaction mixture warmedto rt overnight. The reaction was quenched with water and the solidcollected by filtration. The crude was purified by column chromatography(60-70% EtOAc/hexane) to give2-(4-(3-chlorophenyl)-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(0.22 g), (MS: ESI+ve, 459.17 [M+H]). ¹H NMR: (400 MHz, DMSO) δ: 2.63(s, 3H), 3.24 (s, 3H), 4.73 (s, 2H), 7.44-7.46 (d, J=8.0, 1H), 7.55-7.66(m, 4H), 7.69-7.74 (q, 2H), 7.93 (s, 3H), 8.29-8.31 (d, J=7.2, 1H).

Representative compounds of the invention were prepared in a similarmanner to example 63 from 4-chlorophthalazin-1(2H)-one, thecorresponding boronic acid or ester, and the appropriate alkylatingagent (scheme 2).

64.

2-(4-(3-fluorophenyl)-1- oxophthalazin-2(1H)-yl)-N- methyl-N-(2-methylbenzo[d]oxazol-6- yl)acetamide 443 [M + H]

2-methylbenzo[d]oxazol-6-amine

2-Methyl-6-nitrobenzoxazole (10.0 g, 56 mmol) and 10% PdC (3.4 g) inMeOH (10 mL) were hydrogenated at rt for 16 h. The reaction mixture wasfiltered through Celite and wash with MeOH (100 mL). The filtrate wasconcentrated under vacuum to obtained crude2-methylbenzo[d]oxazol-6-amine (8.4 g), (MS: ESI+ve, 149.07 [M+H]); ¹HNMR: (400 MHz, DMSO) δ: 2.47 (s, 3H), 5.24 (s, 2H), 6.56-6.53 (dd, J=2,1H), 6.70-6.70 (d, J=1.6, 1H), 7.25-7.23 (d, J=8.4, 1H).

2,2,2-trifluoro-N-(2-methylbenzo[d]oxazol-6-yl)acetamide

A solution of 2-methylbenzo[d]oxazol-6-amine (8.4 g, 56.7 mmol) inpyridine (80 mL) at 0° C. was treated with TFAA (19.8 mL, 141.0 mmol)and stirred at rt for 4 h. The reaction mixture was diluted with water(100 mL) and the product extracted with EtOAc (3×100 mL). The organicswere washed with brine, dried over Na₂SO₄, and concentrated to obtainthe crude 2,2,2-trifluoro-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (15.0g), (MS: ESI+ve, 245.20 [M−H]); ¹H NMR: (400 MHz, DMSO) δ: 2.61 (s, 3H),7.61-7.56 (m, 1H), 7.69-7.67 (d, J=8.4, 1H), 8.04-8.04 (d, J=2, 1H),11.45 (s, 1H).

2,2,2-trifluoro-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide

A solution of 2,2,2-trifluoro-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(15.0 g, 61.2 mmol) in DMF (100 mL) was treated with K₂CO₃ (8.448 g,61.2 mmol) and the reaction mixture was stirred at rt for 1 h, thencooled to 0° C. Iodomethane (3.9 mL, 64.2 mmol) was added dropwise andstirring continued at rt overnight. The reaction mixture was dilutedwith water (100 mL) and extracted with EtOAc (3×100 mL). The organicswere washed with brine, dried over Na₂SO₄ and concentrated to obtaincrude 2,2,2-trifluoro-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(16.5 g), (MS: ESI+ve, 259.26 [M+H]).

N,2-dimethylbenzo[d]oxazol-6-amine

To a solution of crude2,2,2-trifluoro-N-methyl-N-(2-methylbenzo[d]oxazol-6-ypacetamide (16.5g, 63.0 mmol) in MeOH (440 mL) and water (73 mL) was added K₂CO₃ (35.3g, 25.5 mmol). The reaction mixture was stirred at reflux for 3 h, thenconcentrated under vacuum, diluted with water (50 mL), extracted withEtOAc (2×50 mL). The organics were washed with brine, dried over Na₂SO₄,and concentrated to obtain crude N,2-dimethylbenzo[d]oxazol-6-amine (8.3g), (MS: ESI+ve, 163.12 [M+H]); ¹H NMR: (400 MHz, DMSO) δ: 2.51 (s, 3H),2.56 (s, 3H), 5.87-5.85 (m, 1H), 6.57-6.53 (m, 1H), 6.65-6.64 (d, J=2.4,1H), 7.31-7.28 (t, 1H).

2-bromo-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide

To a solution of N,2-dimethylbenzo[d]oxazol-6-amine (9.4 g, 58.0 mmol)in DCM (100 mL) was added EDC.HCl (26.6 g, 139 mmol), DMAP (0.354 g, 2.9mmol) and bromoacetic acid (18.5 g, 133.0 mmol) at 0° C. under N₂. Thereaction mixture was stirred at rt overnight, then diluted with water(200 mL). The product was extracted with DCM (3×100 mL) and the organicswere washed with brine, dried over Na₂SO₄ and concentrated to obtain2-bromo-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (10.0 g, 61%),(MS: ESI+ve, 283.1 [M+H]); ¹H NMR: (400 MHz, DMSO) δ: 2.59 (s, 3H), 3.23(s, 3H), 4.04 (s, 2H), 6.76-6.74 (d, J=8.8, 1H), 7.38-7.30 (dd, J=8.8,1H), 7.73-7.71 (d, J=8, 1H).

1,4-dioxo-1,2,3,4-tetrahydrophthalazine-6-carboxylic acid

To a solution of 1,4-dioxo-1,2,3,4-tetrahydrophthalazine-6-carboxylicacid (20 g, 104 mmol) in iPrOH (250 mL) was added hydrazine hydrate(10.40 g, 208 mmol) and the reaction mixture heated to reflux overnight.Upon cooling, the reaction mixture was filtered and the precipitatewashed with iPrOH (100 mL) to obtain1,4-dioxo-1,2,3,4-tetrahydrophthalazine-6-carboxylic acid (25 g, 100%),(MS: ESI+ve, 205.19 [M+H]) ¹H NMR: (400 MHz, DMSO) δ: 8.00-8.02 (dd,J=1.6, 8.4, 1H), 8.24-8.31 (m, 1H), 8.56 (s, 1H).

1-chloro-4-oxo-3,4-dihydrophthalazine-6-carboxylic acid and1-chloro-4-oxo-3,4-dihydrophthalazine-7-carboxylic acid

A solution of 1,4-dioxo-1,2,3,4-tetrahydrophthalazine-6-carboxylic acid(2.0 g) in SO₂Cl₂ (20 mL) was heated to 90° C. for 3 h. POCl₃ (20 mL)was added and heating continued at 110° C. overnight. The solution wasconcentrated under vacuum and distilled with toluene (3×50 mL) to givecrude 1,4-dichlorophthalazine-6-carboxylic acid (1.3 g, 56%), (MS:ESI+ve, 242 [M+H]). This material was dissolved in dioxane (25 mL) andtreated dropwise with 2N NaOH (27 mL) at 0° C. The reaction mixture wasstirred at 50° C. for 1 h, then cooled to rt and concentrated. Water wasadded and acidified with 1N HCl. The solid was filtered and dried undervacuum to give a 1:1 isomeric mixture of1-chloro-4-oxo-3,4-dihydrophthalazine-6-carboxylic acid and1-chloro-4-oxo-3,4-dihydrophthalazine-7-carboxylic acid (0.7 g, 58%),(MS: ESI+ve, 225 [M+H]).

Ethyl 1-chloro-4-oxo-3,4-dihydrophthalazine-6-carboxylate and ethyl1-chloro-4-oxo-3,4-dihydrophthalazine-7-carboxylate

To a solution of a 1:1 mixture of1-chloro-4-oxo-3,4-dihydrophthalazine-6-carboxylic acid and1-chloro-4-oxo-3,4-dihydrophthalazine-7-carboxylic acid (0.7 g) in EtOH(10 mL) was added H₂SO₄ (0.7 mL) and the resulting solution stirred atreflux for 16 h. The reaction was concentrated, water (25 mL) added,treated with sat'd NaHCO₃ (30 mL), and the product extracted with EtOAc(2×100 mL). The organics were washed with brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by column chromatography(10-15% EtOAc/hexane) to give a mixture of ethyl1-chloro-4-oxo-3,4-dihydrophthalazine-6-carboxylate and ethyl1-chloro-4-oxo-3,4-dihydrophthalazine-7-carboxylate (0.550 g, 70%), (MS:ESI+ve, 252.8 [M+H])

Ethyl 1-(3-chlorophenyl)-4-oxo-3,4-dihydrophthalazine-6-carboxylate andEthyl 1-(3-chlorophenyl)-4-oxo-3,4-dihydrophthalazine-7-carboxylate

A mixture of ethyl 1-chloro-4-oxo-3,4-dihydrophthalazine-6-carboxylateand ethyl 1-chloro-4-oxo-3,4-dihydrophthalazine-7-carboxylate (0.5 g,1.98 mmol), (3-chlorophenyl)boronic acid (0.34 g, 2.1 mmol), and K₂CO₃(0.546 g, 3.9 mmol) in dioxane (10 mL) and water (1 mL) was degassedwith argon. It was treated with1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride methylenechloride complex (0.16 g, 0.19 mmol). The reaction was heated to refluxfor 1 hr, then diluted with water (20 mL) and extracted with EtOAc (2×25mL). The organics were dried over Na₂SO₄ and concentrated to give crudeproduct, which was purified by column chromatography (10-15%EtOAc/hexane) to give a mixture of ethyl1-(3-chlorophenyl)-4-oxo-3,4-dihydrophthalazine-6-carboxylate and ethyl1-(3-chlorophenyl)-4-oxo-3,4-dihydrophthalazine-7-carboxylate (0.4 g,61%), (MS: ESI+ve, 328.86 [M+H]).

Examples 65 and 66 Ethyl1-(3-chlorophenyl)-3-(2-(methyl(2-methylbenzo[d]oxazol-6-yl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazine-6-carboxylateand ethyl1-(3-chlorophenyl)-3-(2-(methyl(2-methylbenzo[d]oxazol-6-yl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazine-7-carboxylate

A mixture of ethyl1-(3-chlorophenyl)-4-oxo-3,4-dihydrophthalazine-6-carboxylate and ethyl1-(3-chlorophenyl)-4-oxo-3,4-dihydrophthalazine-7-carboxylate (0.7 g,2.1 mmol) in THF (15 mL) at 0° C. was treated with LiHMDS (1N in THF)(3.2 mL, 3.2 mmol) and stirred for 30 min.2-Bromo-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (0.6 g, 2.1mmol) in THF (10 mL) was added dropwise and the reaction warmed to rtovernight. It was quenched with water (100 mL) and product extractedwith EtOAc (2×100 mL). The organics were washed with brine (50 mL),dried over Na₂SO₄ and concentrated to give crude product, which waspurified by preparative HPLC. Example 65: ethyl1-(3-chlorophenyl)-3-(2-(methyl(2-methylbenzo[d]oxazol-6-yl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazine-6-carboxylate(0.025 g), (MS: ESI+ve, 530.88 [M+H]) ¹H NMR: (400 MHz, DMSO) δ:1.36-1.40 (t, 3H), 2.62 (s, 3H), 3.34 (s, 3H), 4.39-4.44 (q, 2H), 4.78(s, 2H), 7.43-7.45 (d, J=7.2, 1H), 7.56-7.72 (m, 4H), 7.83-7.85 (d,J=8.4, 2H), 7.93 (s, 1H), 8.39-8.41 (t, 1H), 8.77 (s, 1H); Example 66:ethyl1-(3-chlorophenyl)-3-(2-(methyl(2-methylbenzo[d]oxazol-6-yl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazine-7-carboxylate(0.014 g), (MS: ESI+ve, 530.88 [M+H]). ¹H NMR (400 MHz, DMSO) δ:1.30-1.33 (t, 3H), 2.62 (s, 3H), 3.34 (s, 3H), 4.33-4.38 (q, 2H), 4.76(s, 2H), 7.44-7.46 (d, J=7.6, 1H), 7.59-7.74 (m, 5H), 7.94 (s, 1H), 8.20(s, 1H), 8.37-8.43 (q, 2H).

Representative compounds of the invention were prepared in a similarmanner to examples 65 and 66 (scheme 2) using the appropriate alkylatingagent and commercially available boronic acid or boronic ester.

Example No Structure IUPAC Name LCMS m/z 67.

ethyl 1-(3-fluorophenyl)-3-(2- (methyl(2- methylbenzo[d]oxazol-6-yl)amino)-2-oxoethyl)-4-oxo- 3,4-dihydrophthalazine-6- carboxylate 532[M + H] 68.

ethyl 4-(3-fluorophenyl)-2-(2- (methyl(2- methylbenzo[d]oxazol-6-yl)amino)-2-oxoethyl)-1-oxo- 1,2-dihydrophthalazine-6- carboxylate 532[M + H]

3-cyano-N-methoxy-N-methylbenzamide

To a 0° C. solution of 3-cyano benzoic acid (5.0 g, 33.9 mmol) in DMF(30 mL) was added triethylamine (14.8 mL, 101.7 mmol) and EDC.HCl (9.77g, 12.24 mmol). The mixture was stirred at rt for 30 minutes, thencooled again to 0° C. N—O-Dimethylhydroxylamine.HCl (4.97 g, 50.98 mmol)was added and the mixture stirred at rt overnight. The reaction wasquenched with water (300 mL) and extracted with EtOAc (2×100 mL). Theorganic layers was washed with brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by silica gelchromatography (0-25% EtOAc/hexane) to give3-cyano-N-methoxy-N-methylbenzamide (3.2 g, 191 [M+H]). ¹H NMR: (400MHz, DMSO) δ: 3.28 (s, 3H), 3.55 (s, 3H), 7.65-7.69 (t, 1H), 7.89-7.90(d, J=2.4, 1H), 7.96-7.97 (d, J=5.6, 1H), 8.03 (s, 1H).

2-(3-cyanobenzoyl)-5-methoxybenzoic acid

To a solution of 2-bromo-5-methoxybenzoic acid (3.69 g, 15.0 mmol) inTHF (15 mL) was added n-BuLi (1.6 M in hexane) (21 mL, 33.6 mmol)dropwise at −78° C. The reaction mixture was stirred for 1 h at −78° C.,and then a solution of 3-cyano-N-methoxy-N-methylbenzamide (3.2 g, 16.8mmol) in THF (15 mL) was added dropwise. The reaction was stirred for 1h at −78° C. and then overnight at rt. The reaction mixture was dilutedwith water (30 mL) and acidified with 5N HCl solution (10 mL) andextracted with EtOAc (2×100 mL). The organic layer was washed withbrine, dried over Na₂SO₄, and concentrated to obtain2-(3-cyanobenzoyl)-5-methoxybenzoic acid (3.8 g, 282 [M+H]). ¹H NMR:(400 MHz, DMSO) δ: 3.92 (s, 3H), 7.31-7.32 (t, 2H), 7.43-7.45 (t, 2H),7.56 (s, 1H), 7.71-7.72 (d, J=1.6, 1H), 8.10-8.10 (d, J=1.2, 1H), 12.70(s, 1H).

3-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzonitrile

A solution of 2-(3-cyanobenzoyl)-5-methoxybenzoic acid (4.0 g, 14.2mmol) in hydrazine hydrate (8 mL) and EtOH (40 mL) was heated at 110° C.for 2 hr. The reaction mixture was diluted with water (100 mL), and theprecipitate was filtered and dried to yield3-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzonitrile (1.1 g, 278[M+H]). ¹H NMR: (400 MHz, DMSO) δ: 3.96 (s, 3H), 7.28-7.33 (dd, J=2.0,1H), 7.60-7.62 (d, J=8.8, 1H), 7.73-7.78 (m, 2H), 7.92-7.94 (d, J=8.0,1H), 8.01-8.03 (d, J=8.0, 1H), 8.07 (s, 1H), 12.83 (s, 1H).

Example 692-(4-(3-cyanophenyl)-7-methoxy-1-oxophthalazin-2(1H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-methylacetamide

To a solution of3-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzonitrile (0.1 g, 0.36mmol) in DMF (10 mL) was added NaH (60%) (0.021 g, 0.36 mmol)portionwise at 0° C. The reaction mixture was stirred for 30 min at 0°C. 2-Bromo-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl-N-methylacetamide(0.111 g, 0.54 mmol) in DMF (2 mL) was added dropwise at 0° C. and thereaction stirred overnight at rt. The reaction mixture was diluted withsat'd NH₄Cl (25 mL) and extracted with EtOAc (2×25 mL). The organicswere washed with brine (50 mL), dried over Na₂SO₄, and concentrated togive crude which was purified by column chromatography (0-10% EtOAc/DCM)to yield2-(4(3-cyanophenyl)-7-methoxy-1-oxophthalazine-2(1H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-methylacetamide(0.045 g, 505 [M+H]). ¹H NMR: (400 MHz, DMSO) δ: 3.19 (s, 3H), 3.96 (s,3H), 4.77 (s, 2H), 7.34-7.36 (d, J=7.6, 1H), 7.49-7.52 (m, 2H),7.64-7.69 (t, 3H), 7.76-7.80 (t, 1H), 7.91-7.93 (d, J=8.0, 1H),8.03-8.05 (m, 2H).

3-fluoro-N-methoxy-N-methylbenzamide

To a solution of 3-fluorobenzoic acid (30 g, 214.1 mmol) in DCM (300 mL)were added EDC.HCl (45 g, 235 mmol) and N,O-dimethylhydroxylamine.HCl(23 g, 235 mmol) at 0° C. under N₂. The reaction mixture was stirred atrt for 3 h, then diluted with water (1000 mL) and extracted with DCM(3×200 mL). The organics were washed with brine, dried over Na₂SO₄, andconcentrated to obtain the 3-fluoro-N-methoxy-N-methylbenzamide (24 g,61%). (183.91 [M+H]) ¹H NMR: (400 MHz, CDCl₃) δ: 3.38 (s, 3H), 3.57 (s,3H), 7.14-7.19 (m, 1H), 7.37-7.43 (m, 2H), 7.48-7.50 (d, J=7.6, 1H).

2-(3-fluorobenzoyl)-5-methoxybenzoic acid

A −78° C. solution of 2-bromo-5-methoxybenzoic acid (26.0 g, 112.5 mmol)in THF (100 mL) was treated with n-BuLi (1.6 M in hexane) (140 mL, 225mmol) and stirred at −78° C. for 1 h.3-fluoro-N-methoxy-N-methylbenzamide (15.3 g, 83.8 mmol) in THF (40 mL)was added dropwise then warmed to rt for 16 h. The reaction mixture wasdiluted with water (100 mL), acidified with 5N HCl (25 mL) and extractedwith EtOAc (3×200 mL). The organic layer was washed with brine, driedover Na₂SO₄, and concentrated to obtain2-(3-fluorobenzoyl)-5-methoxybenzoic acid (21.0 g, 68%) (274.83 [M+H]);¹H NMR: (400 MHz, DMSO) δ: 3.89 (s, 3H), 7.26-7.29 (m, 1H), 7.37-7.45(m, 4H), 7.50-7.55 (m, 2H).

4-(3-fluorophenyl)-7-methoxyphthalazin-1(2H)-one

A solution of 2-(3-fluorobenzoyl)-5-methoxybenzoic acid (21 g, 76.5mmol) in hydrazine hydrate (4.09 mL, 84.0 mmol) and EtOH (300 mL) washeated overnight at 80° C. The reaction mixture was concentrated,diluted with water (300 mL), and the precipitate was filtered and driedto yield 4-(3-fluorophenyl)-7-methoxyphthalazin-1(2H)-one (7.2 g).(270.85 [M+H]) ¹H NMR: (400 MHz, DMSO) δ: 3.96 (s, 3H), 7.36-7.43 (m,3H), 7.46-7.49 (m, 1H), 7.57-7.64 (m, 2H), 7.73-7.73 (d, J=2.8, 1H).

Example 702-(4-(3-fluorophenyl)-7-methoxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide

A 0° C. solution of 4-(3-fluorophenyl)-7-methoxyphthalazin-1(2H)-one(7.0 g, 25.9 mmol) in THF (160 mL) was treated with LiHMDS (1M in THF)(38 mL, 38 mmol) and stirred for 30 min.2-Bromo-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (7.33 g, 25.9mmol) in THF (40 mL) was added dropwise and stirring was maintained atrt for 16 h. The reaction mixture was diluted with water (200 mL) andthe product extracted with EtOAc (3×150 mL). The organics were washedwith brine (100 mL), dried over Na₂SO₄, and concentrated. The crude wastriturated with MeOH (250 mL) to yield2-(4-(3-fluorophenyl)-7-methoxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(9.1 g, 74%). (472.87 [M+H]) ¹H NMR: (400 MHz, DMSO) δ: 2.62 (s, 3H),3.33 (s, 3H), 4.95 (s, 3H), 4.73 (s, 2H), 7.37-7.43 (m, 4H), 7.48-7.51(d, J=2.4, 8.8, 1H), 7.58-7.73 (m, 4H), 7.90 (s, 1H).

Representative compounds of the invention were prepared in a similarmanner to example 70 from the corresponding 2-bromobenzoic acid,N-methoxy-N-benzamide and appropriate alkylating agent (scheme 5).

Example No. Structure IUPAC Name LCMS m/z 71.

N-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-2-(7-methoxy-1-oxo-4-(4-sulfamoylphenyl)phthalazin-2(1H)- yl)-N-methylacetamide 559 [M + H] 72.

N-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-N-ethyl-2-(7-methoxy-1-oxo-4-(4-sulfamoylphenyl) phthalazin-2(1H)-yl)acetamide 573 [M + H] 73.

N-(4-(difluoromethoxy)phenyl)-N- ethyl-2-(7-methoxy-1-oxo-4-(4-sulfamoylphenyl)phthalazin-2(1H)- yl)acetamide 559 [M + H] 74.

2-(4-(3-cyanophenyl)-7-methoxy-1- oxophthalazin-2(1H)-yl)-N-(4-(difluoromethoxy)phenyl)-N- ethylacetamide 505 [M + H] 75.

2-(4-(3-cyanophenyl)-7-methoxy-1- oxophthalazin-2(1H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N- ethylacetamide 519 [M + H] 76.

N-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)-N-isopropyl-2-(7-methoxy-1-oxo-4-(4- sulfamoylphenyl) phthalazin-2(1H)-yl)acetamide 587[M + H] 77.

2-(4-(3-cyanophenyl)-7-methoxy-1- oxophthalazin-2(1H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N- isopropylacetamide 533 [M + H] 78.

N-cyclopropyl-N-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-2-(7-methoxy-1-oxo-4-(4- sulfamoylphenyl)phthalazin-2(1H)- yl)acetamide585 [M + H] 79.

2-(4-(3-cyanophenyl)-7-methoxy-1- oxophthalazin-2(1H)-yl)-N-cyclopropyl-N-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)acetamide 531 [M +H] 80.

N-ethyl-2-(7-methoxy-1-oxo-4-(4- sulfamoylphenyl)phthalazin-2(1H)-yl)-N-(2-methylbenzo[d]oxazol-6- yl)acetamide 548 [M + H] 81.

2-(4-(3-cyanophenyl)-7-methoxy-1- oxophthalazin-2(1H)-yl)-N-ethyl-N-(2-methylbenzo[d]oxazol-6- yl)acetamide 494 [M + H] 82.

4-(3-(2-((2,2-difluorobenzo[d] [1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-6-methoxy-4-oxo-3,4- dihydrophthalazin-1-yl)benzamide 537 [M +H] 83.

4-(3-(2-((2,2-difluorobenzo[d] [1,3]dioxol-5-yl)(methyl)amino)-2-oxoethyl)-6-methoxy-4-oxo-3,4- dihydrophthalazin-1-yl)benzamide 523 [M +H] 84.

4-(3-(2-(ethyl(2-methylbenzo[d] oxazol-6-yl)amino)-2-oxoethyl)-6-methoxy-4-oxo-3,4- dihydrophthalazin- 1-yl)benzamide 512 [M + H] 85.

2-(4-(3-chlorophenyl)-7-methoxy-1- oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6- yl)acetamide 490 [M + H] 86.

2-(4-(3-cyanophenyl)-7-methoxy-1- oxophthalazin-2(1H)-yl)-N-(methyl-d3)-N-(2-methylbenzo[d]oxazol-6- yl)acetamide 484 [M + H] 87.

2-(4-(3-cyanophenyl)-7-methoxy-1- oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6- yl)acetamide 480 [M + H] 88.

2-(4-(3-chlorophenyl)-7-methoxy-1- oxophthalazin-2(1H)-yl)-N-cyclopropyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 516 [M + H] 89.

2-(4-(3-chlorophenyl)-7-methoxy-1- oxophthalazin-2(1H)-yl)-N-(methyl-d3)-N-(2-methylbenzo[d]oxazol-6- yl)acetamide 493 [M + H] 90.

2-(4-(3-chlorophenyl)-7-methoxy-1- oxophthalazin-2(1H)-yl)-N-(ethyl-1,1-d2)-N-(2-methylbenzo[d]oxazol- 6-yl)acetamide 506 [M + H] 91.

N-ethyl-2-(4-(3-fluorophenyl)-7- methoxy-1-oxophthalazin-2(1H)-yl)-N-(2-methylbenzo[d]oxazol-6- yl)acetamide 488 [M + H] 92.

2-(4-(3-chlorophenyl)-7-methoxy-1- oxophthalazin-2(1H)-yl)-N-ethyl-N-(2-methylbenzo[d]oxazol-6- yl)acetamide 504 [M + H] 93.

2-(6-chloro-4-(3-fluorophenyl)-7- methoxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d] oxazol-6-yl)acetamide 522 [M + H] 94.

2-(6-chloro-4-(3-chlorophenyl)-7- methoxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d] oxazol-6-yl)acetamide 524 [M + H] 95.

N-cyclopropyl-2-(4-(3- fluorophenyl)-7-methoxy-1-oxophthalazin-2(1H)-yl)-N- (2-methylbenzo[d] oxazol-6-yl)acetamide 500[M + H] 96.

2-(6-chloro-4-(3-cyanophenyl)-7- methoxy-1-oxophthalazin-2(1H)-yl)-N-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)-N-methylacetamide 540 [M +H]

2-bromo-4-chloro-5-methoxybenzoic acid

A solution of 4-chloro-3-methoxybenzoic acid (5.0 g, 26.7 mmol) in HOAc(25 mL) and water (25 mL) was treated slowly with Br₂ (1.6 mL 32 mmol).After heating to 60° C. for 2 h, the reaction was stirred cooled to rtovernight. It was quenched with water (300 mL), and the precipitate wasfiltered and dried to yield 2-bromo-4-chloro-5-methoxybenzoic acid (5.0g, 70%). (264.87 [M−H]) ¹H NMR: (400 MHz, DMSO) δ: 3.90 (s, 3H), 7.46(s, 1H), 7.82 (s, 1H), 13.63 (s, 1H).

4-chloro-2-(3-cyanobenzoyl)-5-methoxybenzoic acid

A −78° C. solution of 2-bromo-4-chloro-5-methoxybenzoic acid (0.5 g,1.88 mmol) in THF (15 mL) was treated with n-BuLi (1.6M in hexane) (1.7ml, 2.82 mmol) and stirred for 1 h at −78° C.3-Cyano-N-methoxy-N-methylbenzamide (0.35 g, 1.88 mmol) in THF (15 mL)was added dropwise and the reaction stirred for 1 h at −78° C., thenovernight at rt. It was diluted with water (30 mL), acidified with 5NHCl (15 mL), and extracted with EtOAc (2×100 mL). The organic layer waswashed with brine, dried over Na₂SO₄, and concentrated to obtain4-chloro-2-(3-cyanobenzoyl)-5-methoxybenzoic acid (0.5 g, 84%) (316.33[M−H]).

3-(7-chloro-6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzonitrile

A solution of 4-chloro-2-(3-cyanobenzoyl)-5-methoxybenzoic acid (3.0 g,9.50 mmol) in hydrazine hydrate (0.6 mL 11.4 mmol) and EtOH (40 mL) washeated at 80° C. for 2 h. The reaction mixture was diluted with water(100 mL), and the precipitate was filtered and dried to obtain3-(7-chloro-6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)benzonitrile (0.6g, 17%) (312.4 [M+H]) ¹H NMR: (400 MHz, DMSO) δ: 3.96 (s, 3H), 7.64 (s,1H), 7.79-7.75 (t, 1H), 7.87 (s, 1H), 7.96-7.94 (d, J=8, 1H), 8.04-8.02(d, J=8, 1H), 8.09 (s, 1H), 13.03 (s, 1H).

Example 97 Synthesis of2-(4-(3-fluorophenyl)-7-hydroxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide

To a solution of2-(4-(3-fluorophenyl)-7-methoxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(example 70) (4.0 g, 8.469 mmol) in DCM (30 mL) was added BBr₃ (4.8 mL,50.8 mmol) at 0° C. The reaction mixture was stirred at rt overnightthen diluted with water (150 mL), neutralized with NaHCO₃, thenextracted with DCM (3×100 mL). The organic layer was washed with brine(100 mL), dried over Na₂SO₄, and concentrated to yield2-(4-(3-fluorophenyl)-7-hydroxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(2.9 g, 74%) (459.36 [M+H]).

Representative compounds of the invention were prepared in a similarmanner to example 97 (scheme 6).

Example No. Structure IUPAC Name LCMS m/z  98.

2-(4-(3-chlorophenyl)-7- hydroxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 459 [M + H]  99.

N-cyclopropyl-2-(4-(3- fluorophenyl)-7-hydroxy-1-oxophthalazin-2(1H)-yl)-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 485[M + H] 100.

2-(4-(3-chlorophenyl)-7- hydroxy-1-oxophthalazin-2(1H)-yl)-N-cyclopropyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 502 [M + H]101.

2-(4-(3-chlorophenyl)-7- hydroxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 476 [M + H] 102.

2-(4-(3-cyanophenyl)-7- hydroxy-1-oxophthalazin-2(1H)- yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)-N-methylacetamide 491 [M + H] 103.

2-(4-(3-cyanophenyl)-7- hydroxy-1-oxophthalazin-2(1H)- yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)-N-ethylacetamide 505 [M + H]

Example 104 Synthesis of2-(7-ethoxy-4-(3-fluorophenyl)-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide

Example 97 (6.5 g, 14.19 mmol) was dissolved in DMF (60 mL), treatedwith K₂CO₃ (3.04 g, 21.2 mmol) and stirred at rt for 30 min. Aftercooling to 0° C., EtI (1.26 mL, 15.59 mmol) was added dropwise and thereaction was warmed to rt for 1 h. It was diluted with water (20 mL) andextracted with EtOAc (2×15 mL). The organics were washed with brine (300mL), dried over Na₂SO₄, and concentrated to give crude material whichwas purified by chromatography (40% EtOAc/hexane) to yield2-(7-ethoxy-4-(3-fluorophenyl)-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(3.5 g) (487.52 [M+H]). ¹H NMR: (400 MHz, DMSO) δ: 1.39-1.42 (t, 3H),2.62 (s, 3H), 3.24 (s, 3H), 4.22-4.24 (d, J=7.2, 2H), 4.72 (s, 2H),7.37-7.49 (m, 5H), 7.58-7.65 (m, 3H), 7.71-7.73 (d, J=8.4, 1H), 7.90 (s,1H).

Representative compounds of the invention were prepared in a similarmanner to example 104.

105.

2-(4-(3-chlorophenyl)-7-ethoxy- 1-oxophthalazin-2(1H)-yl)-N-cyclopropyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 530 [M + H] 106.

2-(4-(3-chlorophenyl)-7-ethoxy- 1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 504 [M + H] 107.

2-(4-(3-chlorophenyl)-7- isopropoxy-1-oxophthalazin-2(1H)-yl)-N-(methyl-d3)-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 521[M + H] 108.

N-cyclopropyl-2-(7-ethoxy-4- (3-fluorophenyl)-1-oxophthalazin-2(1H)-yl)-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 514[M + H] 109.

2-(4-(3-cyanophenyl)-7-ethoxy- 1-oxophthalazin-2(1H)-yl)-N- methyl-N-(2-methylbenzo[d]oxazol-6- yl)acetamide 495 [M + H] 110.

2-(7-ethoxy-4-(3-fluorophenyl)- 1-oxophthalazin-2(1H)-yl)-N-(methyl-d3)-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 491 [M + H] 111.

2-(4-(3-chlorophenyl)-7- (cyclopropylmethoxy)-1-oxophthalazin-2(1H)-yl)-N- (methyl-d3)-N-(2- methylbenzo[d]oxazol-6-yl)acetamide 533 [M + H] 112.

2-(4-(3-chlorophenyl)-7- (cyclopropylmethoxy)-1-oxophthalazin-2(1H)-yl)-N- methyl-N-(2- methylbenzo[d]oxazol-6-yl)acetamide 530 [M + H] 113.

2-(4-(3-chlorophenyl)-7- isopropoxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 518 [M +H] 114.

2-(4-(3-chlorophenyl)-7- (cyclohexyloxy)-1- oxophthalazin-2(1H)-yl)-N-methyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 558 [M + H] 115.

2-(4-(3-cyanophenyl)-7- (cyclohexyloxy)-1- oxophthalazin-2(1H)-yl)-N-methyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 549 [M + H] 116.

2-(7-(benzyloxy)-4-(3- chlorophenyl)-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 566 [M +H] 117.

2-(4-(3-fluorophenyl)-1-oxo-7- ((tetrahydro-2H-pyran-4-yl)oxy)phthalazin-2(1H)-yl)-N- methyl-N-(2- methylbenzo[d]oxazol-6-yl)acetamide 544 [M + H] 118.

2-(7-(cyclohexyloxy)-4-(3- fluorophenyl)-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 542 [M +H] 119.

2-(4-(3-chlorophenyl)-1-oxo-7- ((tetrahydro-2H-pyran-4-yl)oxy)phthalazin-2(1H)-yl)-N- methyl-N-(2- methylbenzo[d]oxazol-6-yl)acetamide 560 [M + H] 120.

2-(4-(3-cyanophenyl)-1-oxo-7- ((tetrahydro-2H-pyran-4-yl)oxy)phthalazin-2(1H)-yl)-N- methyl-N-(2- methylbenzo[d]oxazol-6-yl)acetamide 551 [M + H] 121.

2-(6-chloro-7-ethoxy-4-(3- fluorophenyl)-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 508 [M +H] 122.

2-(6-chloro-4-(3-cyanophenyl)- 7-ethoxy-1-oxophthalazin-2(1H)-yl)-N-(2,2- difluorobenzo[d][1,3]dioxol-5- yl)-N-methylacetamide554 [M + H] 123.

2-(6-chloro-4-(3-chlorophenyl)- 7-ethoxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 538 [M +H]

4-Oxo-3,4-dihydrophthalazine-1-carboxylic acid

A solution of 2-methyl acetophenone (5.0 g, 37 mmol) in water (70 mL)was treated with K₂CO₃ (3.0 g, 22 mmol), then heated to reflux and asolution of KMnO₄ (23.5 g, 150 mmol) in water (330 mL) was addeddropwise. After stirring overnight at 90° C., the reaction mixture wasfiltered through Celite and concentrated to half volume. The pH wasadjusted 8 by addition of 2N HCl. It was heated to 90° C. and hydrazinesulfate (4.8 g, 37 mmol) and NaOH (1.66 g, 41 mmol) were added and theheating continued overnight. The reaction volume was reduced to halfvolume and solids filtered. The aqueous layer was acidified with 2N HCland the resulting white precipitate filtered and dried to give4-oxo-3,4-dihydrophthalazine-1-carboxylic acid (1.5 g). ¹H NMR: (400MHz, DMSO) δ: 7.42-7.26 (m, 2H), 7.91-7.80 (m, 2H), 8.46 (s, 1H), 12.85(s, 1H).

Ethyl 4-oxo-3,4-dihydrophthalazine-1-carboxylate

To a solution of 4-oxo-3,4-dihydrophthalazine-1-carboxylic acid (16 g,84.2 mmol) in EtOH was added con H₂SO₄ (40 mL) dropwise. The reactionwas heated to 80° C. overnight. The EtOH was distilled off and water(200 mL) added. The solution was neutralized with NaHCO₃ and thenextracted with EtOAc (3×200 mL). The organic layer was dried over Na₂SO₄and concentrated to give ethyl4-oxo-3,4-dihydrophthalazine-1-carboxylate (15 g, 219 [M+H]). ¹H NMR:(400 MHz, DMSO) δ: 1.37-1.35 (t, 3H), 4.42-4.37 (m, 2H), 7.93-7.88 (m,1H), 8.02-7.97 (m, 1H), 8.31-8.28 (m, 1H), 8.53-8.51 (m, 1H), 13.18 (s,1H).

Ethyl3-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazine-1-carboxylate

To a solution of ethyl 4-oxo-3,4-dihydrophthalazine-1-carboxylate (2.0g, 9.17 mmol) in THF (20 mL) was added NaH (60%) (0.403 g, 10.09 mmol)portionwise at 0° C. The reaction mixture was stirred for 30 min at 0°C., then2-bromo-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethylacetamide (3.044g, 9.17 mmol) was added and the mixture stirred overnight at rt. Thereaction mixture was diluted with water (100 mL) and extracted withEtOAc (3×25 mL). The organic layer was dried over Na₂SO₄ andconcentrated to give ethyl3-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazine-1-carboxylate(3.4 g, 460[M+H]). ¹H NMR: (400 MHz, DMSO) δ: 1.21-1.15 (m, 3H),1.38-1.28 (m, 3H), 4.05-4.00 (q, 2H), 4.45-4.39 (m, 2H), 4.70 (s, 2H),7.37-7.34 (m, 2H), 7.56-7.49 (m, 2H), 7.69-7.68 (d, J=2 Hz, 1H),7.99-7.90(m, 1H), 8.03-8.01(m, 1H), 8.28-8.8.26 (d, J=7.6 Hz, 1H),8.459-8.43 (d, J=8.4 Hz, 1H).

3-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazine-1-carboxylicacid

To a solution of ethyl3-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazine-1-carboxylate(3.4 g, 7.40 mmol) in THF (30 mL) was added 1N NaOH (30 mL, 30 mmol)dropwise at rt. The reaction mixture was stirred at rt overnight,diluted with water (100 mL), neutralized with 2N HCl, and extracted withEtOAc (3×50 mL). The organic layer was dried over Na₂SO₄ andconcentrated to give3-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazine-1-carboxylicacid (2.0 g, 62%). ¹HNMR: (400 MHz, DMSO) δ: 1.10-1.07 (t, J=6.8 Hz,3H), 3.70-3.62 (m, 2H), 4.70 (s, 2H), 7.25-7.23 (d, 1H, J=7.6 Hz),7.36-7.31 (m, 1H), 7.56-7.49 (m, 1H), 8.02-7.90 (m, 2H), 8.28-8.26 (d,J=7.6 Hz, 1H), 8.55-8.53 (d, J=8 Hz, 1H).

Example 124N-(2-cyanophenyl)-3-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazine-1-carboxamide

A solution of3-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazine-1-carboxylicacid (0.150 g, 0.34 mmol) and 2-aminobenzonitrile (0.040 g, 0.34 mmol)in DCM (15 mL) was treated at 0° C. with pyridine (1.0 mL) and stirredfor 15 min. POCl₃ (1.0 mL) was added dropwise and the reaction mixturestirred for 2 hr. The reaction was diluted with water (50 mL),neutralized with sat'd NaHCO₃ (10 mL), and then extracted in EtOAc (3×15mL). The organic layer was dried over Na₂SO₄ to obtain crude product,which was purified by column chromatography (20-25% EtOAc/hexane) togiveN-(2-cyanophenyl)-3-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-4-oxo-3,4-dihydrophthalazine-1-carboxamide(71 mg, 532 [M+H]). ¹H NMR: (400 MHz, DMSO) δ: 1.03-1.06 (t, 3H),3.68-3.73 (q, 2H), 4.76 (s, 2H), 7.36-7.39 (d, J=8.4 Hz, 1H), 7.46-7.50(m, 1H), 7.57-7.59 (d, J=8.8 Hz, 1H), 7.70-7.74 (t, 2H), 7.78-7.82 (m,1H), 7.93-8.05 (m, 3H), 8.31-8.33 (d, J=8 Hz, 1H), 8.71-8.73 (d, J=8.4Hz, 1H), 10.82 (s, 1H).

Representative compounds of the invention were prepared in a similarmanner to example 124 from the corresponding amine and the appropriateside-chain alkylation agent (scheme 6).

Example No. Structure IUPAC Name LCMS m/z 125.

4-chloro-2-(3-(2-((2,2- difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-4-oxo-3,4- dihydrophthalazine-1-carboxamido)benzoic acid 585 [M + H] 126.

3-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-4-oxo-N-(pyridin-2-yl)-3,4-dihydrophthalazine-1- carboxamide 508 [M + H] 127.

3-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-N-methyl-4- oxo-N-(pyridin-2-yl)-3,4-dihydrophthalazine-1-carboxamide 522 [M + H] 128.

N-(5-chloro-2-cyanophenyl)-3-(2-(ethyl(4-ethylphenyl)amino)-2-oxoethyl)- 4-oxo-3,4-dihydrophthalazine-1-carboxamide 514 [M + H] 129.

N-(2-cyanophenyl)-3-(2-((2,2- difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-N-ethyl-4- oxo-3,4-dihydrophthalazine-1-carboxamide 560 [M + H] 130.

methyl 4-chloro-2-(3-(2-(ethyl(4-ethylphenyl)amino)-2-oxoethyl)-4-oxo-3,4- dihydrophthalazine-1-carboxamido)benzoate 548 [M + H]

5-chloro-4-phenylpyridazin-3(2H)-one

To a solution of 4,5-dichloropyridazone (5.0 g, 30.3 mmol) in THF (100mL) was added PhMgBr (1M in THF) (91 mL, 91 mmol) dropwise at 15° C.,then stirred under N₂ at 15° C. for 30 min and at rt for 2 hr. Thereaction mixture was quenched with sat'd NH₄Cl (500 mL) and extractedwith EtOAc (2×250 mL). The organics were washed with brine, dried overNa₂SO₄ and concentrated to give 5-chloro-4-phenylpyridazin-3(2H)-one(5.02 g, 207 [M+H]). ¹H NMR: (400 MHz, DMSO) δ: 7.41-7.50 (m, 5H), 8.11(s, 1H), 13.44 (s, 1H).

2-(4-chloro-6-oxo-5-phenylpyridazin-1(6H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethylacetamide

A 0° C. solution of 5-chloro-4-phenylpyridazin-3(2H)-one (3.0 g, 14.5mmol) in THF (30 mL) was treated with NaH (60%) (0.699 g, 17.4 mmol) andstirred at 0° C. for 30 min. A solution of2-bromo-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethylacetamide (4.68g, 14.5 mmol) in THF (5 mL) was added dropwise and the reaction mixturestirred overnight at rt. It was diluted with sat'd NH₄Cl (200 mL) andextracted with EtOAc (2×250 mL). The extract was washed with brine (300mL), dried over Na₂SO₄ and concentrated to give crude product which waspurified by column chromatography (20-25% EtOAc/hexane) to give2-(4-chloro-6-oxo-5-phenylpyridazin-1(6H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethylacetamide(5.01 g, 448 [M+H]). ¹H NMR: (400 MHz, DMSO) δ: 0.99-1.02 (t, J=6.6 Hz,3H), 3.65-3.67 (q, J=6.4 Hz, 2H), 4.60 (s, 2H), 7.28-7.30 (d, J=8.4 Hz,1H), 7.37-7.48 (m, 5H), 7.53-7.55 (d, J=4.8 Hz, 1H), 7.63 (s, 1H), 8.19(s, 1H).

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(1-oxo-1H-pyridazino[4,5-b]indol-2(5H)-yl)acetamide

To a solution of2-(4-chloro-6-oxo-5-phenylpyridazin-1(6H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethylacetamide(5.0 g, 11.2 mmol) in DMF (40 mL) was added NaN₃ (1.45 g, 22.3 mmol).The reaction was stirred overnight at 110° C., then cooled to rt,diluted with water (100 mL), and extracted with EtOAc (2×250 mL). Theorganics were washed with brine, dried over Na₂SO₄ and concentrated togive a residue which was purified by chromatography (20-25% EtOAcDCM) toyieldN-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(1-oxo-1H-pyridazino[4,5-b]indol-2(5H)-yl)acetamide(3.6 g, 427 [M+H]). ¹H NMR: (400 MHz, DMSO) δ: 1.01-1.05 (t, J=7 Hz,3H), 3.63-3.69 (q, J=7.6 Hz, 2H), 4.71 (s, 2H), 7.26-7.60 (m, 6H),8.13-8.15 (d, J=8 Hz, 1H), 8.39 (s, 1H), 12.30 (s, 1H).

Example 131N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(1-oxo-5-(pyridin-2-ylmethyl)-1H-pyridazino[4,5-b]indol-2(5H)-yl)acetamide

To a solution ofN-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(1-oxo-1H-pyridazino[4,5-b]indol-2(5H)-yl)acetamide(0.200 g, 0.469 mmol) in THF (10 mL) was added NaH (60%) (0.022 g, 0.56mmol) portion wise at 0° C. After stirring 30 min at 0° C.,2-(bromomethyl)pyridine.HBr (0.081 g, 0.516 mmol) was added and thereaction stirred overnight at rt. The reaction mixture was diluted withwater (20 mL) and extracted with EtOAc (2×25 mL). The organics werewashed with brine, dried over Na₂SO₄ and concentrated to give a residuewhich was purified by chromatography (10-12% EtOAcDCM) to giveN-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(1-oxo-5-(pyridin-2-ylmethyl)-1H-pyridazino[4,5-b]indol-2(5H)-yl)acetamide(0.045 g, 519 [M+H]). ¹H NMR: (400 MHz, DMSO) δ: 1.02-1.05 (t, J=7, 3H),3.71-3.65 (qt, J=6.8, 13.6, 2H), 4.73 (s, 2H), 5.89 (s, 2H), 7.31-7.28(m, 1H), 7.40-7.34 (m, 3H), 7.55-7.48 (m, 2H), 7.700 (s, 1H), 7.81-7.7(m, 2H), 8.18-8.16 (d, J=7.6, 1H), 8.47-8.46 (dd, J=0.8, 5.2, 1H),8.73(s, 1H).

Representative compounds of the invention were prepared in a similarmanner to examples 131 (scheme 5).

Example No. Structure IUPAC Name LCMS m/z 132.

N-(2,2-difluorobenzo[d][1,3]dioxol-5- yl)-N-ethyl-2-(5-(2-methoxyethyl)-1-oxo-1H-pyridazino[4,5-b]indol- 2(5H)-yl)acetamide 485 [M + H] 133.

2-(5-benzyl-1-oxo-1H-pyridazino[4,5- b]indol-2(5H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N- ethylacetamide 517 [M + H] 134.

methyl 3-(2-(2-((2,2-difluorobenzo[d] [1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-1-oxo-1H-pyridazino[4,5-b] indol-5(2H)- yl)propanoate 513 [M +H] 135.

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-ethyl-2-(5-(3-methoxybenzyl)-1-oxo-1H-pyridazino[4,5-b]indol-2(5H)- yl)acetamide 547 [M + H] 136.

N-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-N-ethyl-2-(5-(4-methoxybenzyl)-1-oxo-1H- pyridazino[4,5-b]indol-2(5H)- yl)acetamide 547[M + H] 137.

N-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-N-ethyl-2-(5-(3-methoxypropyl)-1-oxo-1H- pyridazino[4,5-b]indol-2(5H)- yl)acetamide 499[M + H] 138.

2-(5-(2-cyanoethyl)-1-oxo-1H- pyridazino[4,5-b]indol-2(5H)-yl)-N-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-N-ethylacetamide 480 [M + H]139.

2-(5-(cyanomethyl)-1-oxo-1H- pyridazino[4,5-b]indol-2(5H)-yl)-N-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)-N-ethylacetamide 466 [M + H]140.

N-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-N-ethyl-2-(1-oxo-5-(pyridin-3-ylmethyl)-1H-pyridazino[4,5-b] indol-2(5H)-yl)acetamide 518 [M + H] 141.

2-(5-(2-cyanobenzyl)-1-oxo-1H- pyridazino[4,5-b]indol-2(5H)-yl)-N-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)-N-ethylacetamide 542 [M +H] 142.

2-(5-(3-cyanobenzyl)-1-oxo-1H- pyridazino[4,5-b]indol-2(5H)-yl)-N-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)-N-ethylacetamide 542 [M +H] 143.

N-(2,2-difluorobenzo[d][1,3]dioxol- 5-yl)-N-ethyl-2-(1-oxo-5-(pyridin-4-ylmethyl)-1H-pyridazino[4,5-b]indol- 2(5H)-yl)acetamide 518 [M + H] 144.

2-(5-(4-cyanobenzyl)-1-oxo-1H- pyridazino[4,5-b]indol-2(5H)-yl)-N-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)-N-ethylacetamide 542 [M + H]145.

2-(5-(4-cyano-3-fluorobenzyl)- 1-oxo-1H-pyridazino[4,5-b]indol-2(5H)-yl)-N-(2,2- difluorobenzo[d][1,3]dioxol- 5-yl)-N-ethylacetamide560 [M + H] 146.

2-(5-(4-cyano-2-fluorobenzyl)- 1-oxo-1H-pyridazino[4,5-b]indol-2(5H)-yl)-N-(2,2- difluorobenzo[d][1,3]dioxol- 5-yl)-N-ethylacetamide560 [M + H] 147.

2-(5-(4-chlorobenzyl)-1-oxo- 1,5-dihydro-2H-pyridazino[4,5-b]indol-2-yl)-N-methyl-N-(2- methylbenzo[d]oxazol-6-yl)acetamide 513 [M +H] 148.

2-(5-(4-fluorobenzyl)-1-oxo- 1,5-dihydro-2H-pyridazino[4,5-b]indol-2-yl)-N-methyl-N-(2- methylbenzo[d]oxazol-6-yl) acetamide 496[M + H] 149.

2-(5-(4-cyanobenzyl)-1-oxo- 1,5-dihydro-2H-pyridazino[4,5-b]indol-2-yl)-N-methyl-N-(2- methylbenzo[d]oxazol-6- yl)acetamide 504[M + H]

Example 150 Synthesis of5-methyl-1-(piperidine-1-carbonyl)-3-p-tolyl-3H-pyridazino[4,5-b]indol-4(5H)-one

Ethyl 1-methyl-1H-indole-2-carboxylate

Ethyl 1H-indole-2-carboxylate (5.0 g, 26.45 mmol) was dissolved in DMF(40 mL), then NaH (60%) (1.58 g, 39.68 mmol) was added at 0° C. Afterstirring for 20 min at this temperature, iodomethane (8.27 mL, 13.22mmol) was added dropwise and the reaction stirred at rt overnight. Itwas partitioned between sat'd NH₄Cl (100 mL) and diethyl ether (100 mL),and the aqueous layer was further extracted with diethyl ether (2×50mL). The organic layers were combined and dried (Na₂SO₄), then thesolvent was removed in vacuo to obtain ethyl1-methyl-1H-indole-2-carboxylate (4.0 g, 74%).

Ethyl 3-(2-ethoxy-2-oxoacetyl)-1-methyl-1H-indole-2-carboxylate

To a solution of ethyl chloro oxoacetate (0.60 mL, 5.41 mmol) in DCE (30mL) was added TiCl₄ (0.59 mL, 5.41 mmol) at rt, and the reaction stirredfor 30 min at rt. Ethyl 1-methyl-1H-indole-2-carboxylate (1.0 g, 4.92mmol) in DCE was added dropwise and the reaction stirred for 3 hr at rt.The reaction was quenched with sat'd NH₄Cl solution (50 mL) andextracted with DCM (25 mL×3). The organic layer was dried over Na₂SO₄and concentrated to give ethyl3-(2-ethoxy-2-oxoacetyl)-1-methyl-1H-indole-2-carboxylate (1.0 g). MS:ESI+ve, 304.6 [M+H].

5-Methyl-4-oxo-3-p-tolyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate

To a solution of ethyl3-(2-ethoxy-2-oxoacetyl)-1-methyl-1H-indole-2-carboxylate (0.9 g, 3.11mmol) in HOAc (20 mL) was added p-tolylhydrazine hydrochloride (0.6 g,3.92 mmol). The reaction mixture was heated at 100° C. overnight, thenthe reaction was quenched with water (5 mL) and neutralized with sat'dNaHCO₃ (10 mL). The aqueous layered was extracted with EtOAc (3×30 mL),and the combined organic layers dried with Na₂SO₄, then concentrated.The crude product was purified by column chromatography (10-50%EtOAc/hexane) to give ethyl5-methyl-4-oxo-3-p-tolyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate(0.33 g). MS: ESI+ve, 348.69 [M+H].

Example 150 of5-methyl-1-(piperidine-1-carbonyl)-3-p-tolyl-3H-pyridazino[4,5-b]indol-4(5H)-one

Me₃Al (2M in toluene, 1.05 mL, 2.07 mmol) was added dropwise to astirred solution of piperidine (0.107 g, 1.24 mmol) in toluene (5 mL).After stirring the mixture for 2 hr at rt, ethyl5-methyl-4-oxo-3-p-tolyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate(0.150 g, 0.41 mmol) was added and the reaction heated to 110° C. for 2h. The reaction was quenched with water (15 mL) and extracted with EtOAc(3×20 mL). The organic layer was dried over Na₂SO₄, then concentrated toobtain crude material, which was purified by column chromatography(5-50% EtOAc/hexane) to yield5-methyl-1-(piperidine-1-carbonyl)-3-p-tolyl-3H-pyridazino[4,5-b]indol-4(5H)-one(0.036 g); MS: ESI+ve, 401.34 [M+H]. ¹H NMR (DMSO-d₆) δ 7.84 (m, 2H),7.64 (m, 1H), 7.45 (m, 3H), 7.33 (m, 2H), 4.34 (s, 3H), 3.77 (m, 2H),3.43 (q, 2H), 2.40 (s, 3H), 1.65 (m, 4H), 1.37 (m, 2H).

Representative compounds of the invention were prepared in a similarmanner to example 150 (scheme 7).

Example No. Structure IUPAC Name LCMS m/z 151.

N-ethyl-5-methyl-4-oxo-3- phenyl-N-(pyrimidin-4-yl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 439 [M + H] 152.

N-isopropyl-5-methyl-4-oxo- N-phenyl-3-(p-tolyl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 451 [M + H] 153.

N-cyclopropyl-5-methyl-4- oxo-N-phenyl-3-(p-tolyl)-4,5-dihydro-3H-pyridazino[4,5-b] indole-1-carboxamide 449 [M + H] 154.

N-(cyanomethyl)-5-methyl- 4-oxo-N-phenyl-3-(p-tolyl)- 4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 448 [M + H] 155.

N,N-diethyl-5-methyl-4- oxo-3-(p-tolyl)-4,5-dihydro-3H-pyridazino[4,5-b]indole- 1-carboxamide 389 [M + H] 156.

N-ethyl-5-methyl-4-oxo-N- (pyridin-2-yl)-3-(p-tolyl)-4,5-dihydro-3H-pyridazino[4,5-b] indole-1-carboxamide 438 [M + H] 157.

N-ethyl-5-methyl-4-oxo-N- (pyridin-3-yl)-3-(p-tolyl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 438 [M + H] 158.

N-ethyl-5-methyl-4-oxo-3- phenyl-N-(pyridin-4-yl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 438 [M + H] 159.

5-methyl-1-(1,2,3,4- tetrahydroquinoline-1- carbonyl)-3-(p-tolyl)-3H-pyridazino[4,5-b]indol- 4(5H)-one 449 [M + H] 160.

N-cyclopropyl-N-ethyl-5- methyl-4-oxo-3-(p-tolyl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 401 [M + H] 161.

1-(4-benzylpiperazine-1- carbonyl)-5-methyl-3-(p-tolyl)-3H-pyridazino[4,5- b]indol-4(5H)-one 492 [M + H] 162.

N-ethyl-5-methyl-4-oxo-3- phenyl-N-(pyrimidin-2-yl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 439 [M + H] 163.

2-(5-methyl-4-oxo-N- phenyl-3-(p-tolyl)-4,5- dihydro-3H-pyridazino[4,5-b]indole-1- carboxamido)acetic acid 467 [M + H] 164.

N-ethyl-5-methyl-N-(1- methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-oxo-3- phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 493 [M + H] 165.

8-chloro-N-ethyl-5-methyl- 4-oxo-N-phenyl-3-(p-tolyl)- 4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 472 [M + H] 166.

7-chloro-N-ethyl-5-methyl- 4-oxo-N-phenyl-3-(p-tolyl)- 4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 472 [M + H] 167.

N-ethyl-5-methyl-4-oxo-N- phenyl-3-(pyridin-2-yl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 424 [M + H] 168.

3-benzyl-N-ethyl-5-methyl- 4-oxo-N-phenyl-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 424 [M + H] 169.

N-ethyl-5-methyl-4-oxo-N- phenyl-3-(pyridin-4-yl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 424 [M + H] 170.

N-ethyl-5-methyl-4-oxo-N- phenyl-3-(thiazol-2-yl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 430 [M + H] 171.

N-ethyl-5-methyl-4-oxo-N- phenyl-3-(pyrimidin-2-yl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 425 [M + H] 172.

3-(benzo[d]thiazol-2-yl)-N- ethyl-5-methyl-4-oxo-N-phenyl-4,5-dihydro-3H- pyridazino[4,5-b]indole-1- carboxamide 480 [M +H] 173.

N-ethyl-5-methyl-3-(1- methyl-1H-benzo[d] imidazol-2-yl)-4-oxo-N-phenyl-4,5-dihydro- 3H-pyridazino[4,5-b]indole- 1-carboxamide 477[M + H] 174.

N-ethyl-3-(2-fluorophenyl)- 5-methyl-4-oxo-N-phenyl-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 441 [M + H] 175.

N-ethyl-N-(3-fluorophenyl)- 5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 442 [M + H] 176.

N-ethyl-3-(2-fluorophenyl)- 5-methyl-4-oxo-N-phenyl-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 441 [M + H] 177.

N-ethyl-5-methyl-4-oxo-N- phenyl-3-(quinolin-3-yl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 474 [M + H] 178.

3-(4-chlorophenyl)-N-ethyl- 5-methyl-4-oxo-N-phenyl-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 457 [M + H] 179.

N-ethyl-3-(4- methoxyphenyl)-5-methyl- 4-oxo-N-phenyl-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 453 [M + H] 180.

N-ethyl-5-methyl-3-(5- methylpyridin-2-yl)-4-oxo-N-phenyl-4,5-dihydro-3H- pyridazino[4,5-b]indole-1- carboxamide 438 [M +H] 181.

N-(3-chlorophenyl)-N-ethyl- 5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 457 [M + H] 182.

N-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)-N-ethyl-5-methyl-4-oxo-3-(p-tolyl)-4,5- dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide 517 [M + H] 183.

4-chloro-2-(N-ethyl-5- methyl-4-oxo-3-(p-tolyl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamido) benzoic acid 515 [M +H] 184.

4-chloro-2-(5-methyl-4-oxo- 3-(p-tolyl)-4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamido)benzoic acid 487 [M + H] 185.

N-ethyl-5-methyl-4-oxo-N- phenyl-3-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-3H- pyridazino[4,5-b]indole-1- carboxamide 431[M + H] 186.

N-isopropyl-5-methyl-4-oxo- N-phenyl-3-(pyridin-2-yl)- 4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 438 [M + H] 187.

N-ethyl-8-methoxy-5- methyl-4-oxo-N-phenyl-3- (p-tolyl)-4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 467 [M + H] 188.

N-ethyl-7-methoxy-5- methyl-4-oxo-N-phenyl-3- (p-tolyl)-4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 467 [M + H] 189.

N-ethyl-6-methoxy-5- methyl-4-oxo-N-phenyl-3- (p-tolyl)-4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 467 [M + H] 190.

N-(4-chlorophenyl)-N- isopropyl-5-methyl-4-oxo-3- phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 471 [M + H] 191.

N-isopropyl-5-methyl-4-oxo- N-phenyl-3-(quinolin-3-yl)- 4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 488 [M + H] 192.

3-(3-chloro-4- methoxyphenyl)-N-ethyl-5- methyl-4-oxo-N-(pyridin-2-yl)-4,5-dihydro-3H- pyridazino[4,5-b]indole- 1-carboxamide 488 [M + H]193.

N-ethyl-5-methyl-4-oxo-N- phenyl-3-(5- (trifluoromethyl)pyridin-2-yl)-4,5-dihydro-3H- pyridazino[4,5-b]indole-1- carboxamide 492 [M + H]194.

N-ethyl-5-methyl-4-oxo-N- phenyl-3-(4- (trifluoromethyl)phenyl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 491 [M + H] 195.

N-ethyl-9-methoxy-5- methyl-4-oxo-N-phenyl-3- (p-tolyl)-4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 467 [M + H] 196.

N-ethyl-5,9-dimethyl-4-oxo- N-phenyl-3-(p-tolyl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 451 [M + H]

Example 197 Synthesis of3-benzyl-N-ethyl-5-methyl-4-oxo-N-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide

5-Methyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate

To a solution of ethyl3-(2-ethoxy-2-oxoacetyl)-1-methyl-1H-indole-2-carboxylate (0.5 g, 1.65mmol) in HOAc (6.0 mL) was added hydrazine hydrate (0.123 g, 2.47 mmol)and the reaction stirred at 110° C. overnight. The reaction was quenchedwith water (50 mL) and the precipitate collected and dried to give ethyl5-methyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate(0.33 g) as solid. MS: ESI+ve, 273.18 [M+H].

Ethyl3-benzyl-5-methyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate

NaH (60%) (0.062 g, 1.54 mmol) was added a solution of ethyl5-methyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate(0.35 g, 1.29 mmol) in THF (5 mL) at 0° C. and stirred at rt for 30 min.The reaction was cooled to 0° C. again, then Bn—Br (0.17 mL, 1.42 mmol)added and the mixture stirred at rt for 12 hr. The reaction was quenchedwith water (20 mL) and extracted with EtOAc (3×20 mL). The combinedorganic layers were dried over Na₂SO₄, and concentrated. The crudeproduct was purified by column chromatography (20% EtOAc/hexane) to giveethyl3-benzyl-5-methyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate(0.25 g, 53%) as a solid. MS: ESI+ve, 362.24 [M+H].

Example 1973-benzyl-N-ethyl-5-methyl-4-oxo-N-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide

Me₃Al (2M in toluene, 1.05 mL, 2.07 mmol) was added dropwise to astirred solution of N-ethyl aniline (0.15 g, 1.24 mmol) in toluene (5mL). After stirring the mixture for 2 hr at rt, ethyl3-benzyl-5-methyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate(0.150 g, 0.42 mmol) was added and the reaction heated to 110° C. for 2h. The reaction was quenched with water (20 mL), neutralized with asatd. solution of NaHCO3 (15 mL) and extracted with EtOAc (3×25 mL). Theorganic layer was dried over Na₂SO₄, concentrated, and purified bycolumn chromatography (0-30% EtOAc/hexane) to yield3-benzyl-N-ethyl-5-methyl-4-oxo-N-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide(0.060 g). MS: ESI+ve, 437.31 [M+H]. ¹H NMR (DMSO-d₆) δ 8.02 (d, J=8 Hz,1 H), 7.80 (m, 1 H), 7.68 (m, 1 H), 7.49 (m, 1 H), 7.24 (m, 3 H), 7.19(m, 3 H), 7.05 (m, 2 H), 6.85 (m, 2 H), 5.14 (s, 2 H), 4.23 (s, 3 H),4.05 (q, J=7 Hz, 2 H), 1.23 (t, J=7 Hz, 3 H).

Representative compounds of the invention were prepared in a similarmanner to example 197 (scheme 8).

Example No. Structure IUPAC Name LCMS m/z 198.

3-(1-benzylpiperidin-4-yl)-N- ethyl-5-methyl-4-oxo-N-phenyl-4,5-dihydro-3H- pyridazino[4,5-b]indole-1- carboxamide 520 [M +H] 199.

N-ethyl-5-methyl-3-(1- methylpiperidin-4-yl)-4-oxo-N-phenyl-4,5-dihydro-3H- pyridazino[4,5-b]indole-1- carboxamide 444 [M +H] 200.

3-(1-((2,2-difluorobenzo[d][1,3] dioxol-5-yl)sulfonyl)piperidin-4-yl)-N-ethyl-5-methyl-4-oxo- N-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 650 [M + H] 201.

N-(3-chlorophenyl)-N-ethyl-3- isopropyl-5-methyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5-b] indole-1-carboxamide 423 [M + H] 202.

N-(3-chlorophenyl)-3-(2-((2,2- difluorobenzo[d][1,3]dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-N- ethyl-5-methyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5-b] indole-1-carboxamide 623 [M + H] 203.

N-(3-chlorophenyl)-N-ethyl-3- (2-(ethyl(4-ethylphenyl)amino)-2-oxoethyl)-5-methyl-4-oxo- 4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide 571 [M + H] 204.

N-(3-chlorophenyl)-3- cyclohexyl-N-ethyl-5-methyl-4- oxo-4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 463 [M + H] 205.

N-(5-chloro-2-cyanophenyl)-N- ethyl-3-isopropyl-5-methyl-4-oxo-4,5-dihydro-3H- pyridazino[4,5-b]indole-1- carboxamide 448 [M + H]206.

3-(2-((2,2-difluorobenzo[d][1,3] dioxol-5-yl)(ethyl)amino)-2-oxoethyl)-N,N-diethyl-5- methyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 540 [M + H] 207.

N-ethyl-3,5-dimethyl-4-oxo-N- phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 361 [M + H] 208.

3-isopropyl-5-methyl-1- (piperidine-1-carbonyl)-3,5-dihydro-4H-pyridazino[4,5-b] indol-4-one 353 [M + H] 209.

N-(3-chlorophenyl)-N-ethyl- 3,5-dimethyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 395 [M + H] 210.

N-(4-ethoxyphenyl)-N-ethyl-3- isopropyl-5-methyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5-b] indole-1-carboxamide 433 [M + H] 211.

N-(2,2- difluorobenzo[d][1,3]dioxol-5- yl)-N-ethyl-3,5-dimethyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 441 [M + H] 212.

3-benzyl-N-isopropyl-5-methyl- 4-oxo-N-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 451 [M + H] 213.

3-(2-((3- chlorophenyl)(ethyl)amino)-2- oxoethyl)-N,N-diethyl-5-methyl-4-oxo-4,5-dihydro-3H- pyridazino[4,5-b]indole-1- carboxamide 494[M + H] 214.

N-ethyl-5-methyl-4-oxo-3-(2- oxo-2-(piperidin-1-yl)ethyl)-N-phenyl-4,5-dihydro-3H- pyridazino[4,5-b]indole-1- carboxamide 472 [M +H] 215.

N-ethyl-5-methyl-3-(2- morpholino-2-oxoethyl)-4-oxo-N-phenyl-4,5-dihydro-3H- pyridazino[4,5-b]indole-1- carboxamide 474 [M +H] 216.

N-ethyl-5-methyl-4-oxo-N- phenyl-3-((THF-2-yl)methyl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 431 [M + H] 217.

N-ethyl-5-methyl-3-neopentyl- 4-oxo-N-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 417 [M + H] 218.

N-ethyl-5,9-dimethyl-4-oxo-N- phenyl-3-(1-phenylethyl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 465 [M + H]

Example 2195-cyclobutyl-N-ethyl-4-oxo-N-phenyl-3-p-tolyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide

Ethyl 3-(2-ethoxy-2-oxoacetyl)-1H-indole-2-carboxylate

TiCl₄ (1.3 mL, 11.6 mmol) was added to a solution of ethyl chlorooxoacetate (1.3 mL, 11.6 mmol) in DCE (40 mL) and the reaction stirredfor 30 min at rt. A solution of ethyl 1H-indole-2-carboxylate (2.0 g,10.5 mmol) in DCE was added dropwise and stirring was continued for 2hr. The reaction was quenched with water (100 mL) and extracted with DCM(3×100 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated to give ethyl3-(2-ethoxy-2-oxoacetyl)-1H-indole-2-carboxylate (2.64 g). MS: ESI+ve,289.94 [M+H].

Ethyl4-oxo-3-p-tolyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate

To a solution ethyl 3-(2-ethoxy-2-oxoacetyl)-1H-indole-2-carboxylate(2.64 g, 9.13 mmol) in HOAc (40 mL) was added p-tolylhydrazinehydrochloride (1.82 g, 11.5 mmol), and reaction was heat at 100° C.overnight. The reaction was quenched with water (50 mL), and the solidproduct collected by filtration to yield ethyl4-oxo-3-p-tolyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate(2.5 g). MS: ESI+ve, 347.98 [M+H].

Example 220N-Ethyl-4-oxo-N-phenyl-3-p-tolyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide

Me₃Al (2.0 M in toluene, 7.2 mL, 14.4 mmol) was added dropwise to astirred solution of N-ethyl aniline (1.04 g, 8.64 mmol) in toluene (20mL). After stirring the mixture for 2 hr at rt, ethyl4-oxo-3-p-tolyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate(1.0 g, 2.88 mmol) was added and the reaction heated to 100° C. for 2 h.The reaction was quenched with water (50 mL), neutralized with a satd.solution of NaHCO₃ (100 mL) and extracted with EtOAc (3×75 mL). Theorganic layer was dried over Na₂SO₄, then concentrated, and purified bycolumn chromatography (40% EtOAc/hexane) to giveN-ethyl-4-oxo-N-phenyl-3-p-tolyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide(0.4 g). MS: ESI+ve, 423.68 [M+H]. ¹H NMR (DMSO-d₆) δ 13.1 (s, 1 H),8.08 (d, J=8 Hz, 1 H), 7.68-7.22 (m, 8 H), 7.08 (m, 2 H), 6.91 (m, 2 H),4.05 (q, 2 H), 1.25 (t, J=7 Hz, 3 H).

Example 2195-cyclobutyl-N-ethyl-4-oxo-N-phenyl-3-p-tolyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide

K₂CO₃ (0.122 g, 0.88 mmol) was added to a solution ofN-ethyl-4-oxo-N-phenyl-3-p-tolyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide(0.25 g, 0.59 mmol) in acetonitrile (5.0 mL) at rt. After stirring for30 min, bromo cyclobutane (0.48 g, 3.55 mmol) was added and the reactionheated to reflux overnight. The reaction was quenched with water (50 mL)and extracted with EtOAc (3×40 mL). The organic layer was dried overNa₂SO₄, then concentrated to obtain crude product, which was purified bycolumn chromatography (15% EtOAc/hexane) to give5-cyclobutyl-N-ethyl-4-oxo-N-phenyl-3-p-tolyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide(11.5 mg). MS: ESI+ve, 477.34 [M+H]. ¹H NMR (CD₃CN) δ 8.18 (m, 1 H),8.12 (m, 1 H), 7.66 (m, 1 H), 7.50 (m, 1 H), 7.24 (m, 5 H), 7.08 (m, 2H), 6.97 (m, 2 H), 6.47 (m, 1 H), 4.09 (q, J=7 Hz, 2 H), 3.13 (m, 2 H),2.47 (m, 2 H), 2.41 (s, 3 H), 2.10 (m, 2 H), 1.32 (t, J=7 Hz, 3 H).

Representative compounds of the invention were prepared in a similarmanner to example 219 (scheme 9).

Example No. Structure IUPAC Name LCMS m/z 221.

N-(3-chlorophenyl)-N-ethyl- 4-oxo-3-(p-tolyl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 457 [M + H] 222.

N-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)-N-ethyl-2-(4-oxo-4,5-dihydro-3H- pyridazino[4,5-b]indol-3- yl)acetamide 427 [M + H]223.

5-(cyanomethyl)-N-ethyl-4- oxo-N-phenyl-3-(p-tolyl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 462 [M + H] 224.

2-(1- (ethyl(phenyl)carbamoyl)-4- oxo-3-(p-tolyl)-3H-pyridazino[4,5-b]indol- 5(4H)-yl)acetic acid 481 [M + H] 225.

N-ethyl-5-isopropyl-4-oxo-N- phenyl-3-(p-tolyl)-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 465 [M + H] 226.

N-ethyl-4-oxo-N-phenyl-5- (pyridin-2-ylmethyl)-3-(p-tolyl)-4,5-dihydro-3H- pyridazino[4,5-b]indole-1- carboxamide 514 [M +H] 227.

N-ethyl-3-(2-methoxyethyl)- 5-methyl-4-oxo-N-phenyl- 4,5-dihydro-3H-pyridazino[4,5-b]indole-1- carboxamide 405 [M + H] 228.

(R)-N-ethyl-3-(2-hydroxy-3- methoxypropyl)-5-methyl-4-oxo-N-phenyl-4,5-dihydro- 3H-pyridazino[4,5-b]indole-1- carboxamide 435[M + H] 229.

(R)-3-(2,3-dihydroxypropyl)- N-ethyl-5-methyl-4-oxo-N-phenyl-4,5-dihydro-3H- pyridazino[4,5-b]indole-1- carboxamide 421 [M +H] 230.

(R)-3-(3-(benzyloxy)-2- hydroxypropyl)-N-ethyl-5-methyl-4-oxo-N-phenyl-4,5- dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide 511 [M + H] 231.

3-(3-(benzyloxy)-2- hydroxypropyl)-N,N-diethyl-9-methoxy-5-methyl-4-oxo- 4,5-dihydro-3H- pyridazino[4,5-b]indole-1-carboxamide 493 [M + H] 232.

3-(3-(benzyloxy)-2- hydroxypropyl)-N,N-diethyl- 5,9-dimethyl-4-oxo-4,5-dihydro-3H-pyridazino[4,5- b]indole-1-carboxamide 477 [M + H] 233.

3-(3-(benzyloxy)-2- hydroxypropyl)-9-chloro-N,N-diethyl-5-methyl-4-oxo-4,5- dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide 498 [M + H] 234.

3-(3-(benzyloxy)-2- hydroxypropyl)-N,N-diethyl-9-fluoro-5-methyl-4-oxo-4,5- dihydro-3H-pyridazino[4,5-b]indole-1-carboxamide 481 [M + H]

Example 235 Synthesis of1,3-diphenyl-3H-pyridazino[4,5-b]indol-4(5H)-one

3-Benzoyl-1-methyl-1H-indole-2-carboxylate

AlCl₃ (0.65 g, 0.49 mmol) was added to a stirred solution of ethyl1-methyl-1H-indole-2-carboxylate (1.0 g, 0.49 mmol) in DCE (10.0 mL),followed by benzoyl chloride (0.57 mL, 0.49 mmol). The reaction washeated to reflux overnight, then quenched with water (50 mL),neutralized with a satd. solution of NaHCO₃ (100 mL), and extracted withEtOAc (3×100 mL). The combined organic layers were dried over Na_(s)SO₄and concentrated to obtained crude product, which was purified by columnchromatography (7% EtOAc/hexane) to yield ethyl3-benzoyl-1-methyl-1H-indole-2-carboxylate (0.5 g). MS: ESI+ve, 309.25[M+H].

1,3-Diphenyl-3H-pyridazino[4,5-b]indol-4(5H)-one (Example 235):

Phenyl hydrazine (0.105 g, 0.97 mmol) was added to a stirred solution ofethyl 3-benzoyl-1-methyl-1H-indole-2-carboxylate (0.2 g, 0.65 mmol) inHOAc (6.0 mL) and the reaction refluxed overnight. The reaction wasquenched with water (10 mL), neutralized with satd. NaHCO₃ (20 mL) andextracted with EtOAc (3×30 mL). The combined organic layers were driedwith Na₂SO₄ and concentrated to obtained crude product, which waspurified by column chromatography (10% EtOAc/hexane) to yield1,3-diphenyl-3H-pyridazino[4,5-b]indol-4(5H)-one (0.02 g). MS: ESI+ve,352.27 [M+H]. ¹H NMR (DMSO-d₆) δ 7.85 (d, J=8 Hz, 1 H), 7.76-7.68 (m, 4H), 7.62-7.60 (m, 4 H), 7.58 (m, 2 H), 7.46-7.40 (m, 2 H), 7.26 (m, 1H), 4.38 (s, 3 H).

Representative compounds of the invention were prepared in a similarmanner to example 235 (scheme 10).

Example No. Structure IUPAC Name LCMS m/z 236.

5-methyl-1-phenyl-3-(p-tolyl)- 3H-pyridazino[4,5-b]indol- 4(5H)-one 366[M + H] 237.

3-(2-fluorophenyl)-5-methyl-1- phenyl-3H-pyridazino[4,5-b]indol-4(5H)-one 370 [M + H] 238.

N-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)-N-ethyl-2-(5-methyl-4-oxo-1-(pyridin- 3-ylmethyl)-4,5-dihydro-3H-pyridazino[4,5-b]indol- 3-yl)acetamide 532 [M + H] 239.

3-isopropyl-5-methyl-1-phenyl- 3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one 318 [M + H] 240.

3-(3-isopropyl-5-methyl-4-oxo- 4,5-dihydro-3H-pyridazino[4,5-b]indol-1-yl)benzonitrile 341 [M + H] 241.

3-cyclohexyl-5-methyl-1- phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one 358 [M + H] 242.

1-((1H-imidazol-1-yl)methyl)-5- methyl-3-(p-tolyl)-3,5-dihydro-4H-pyridazino[4,5-b]indol-4- one 370 [M + H] 243.

5-methyl-1- (morpholinomethyl)-3-(p-tolyl)-3,5-dihydro-4H-pyridazino[4,5- b]indol-4-one 389 [M + H] 244.

3-(3-cyclohexyl-5-methyl-4- oxo-4,5-dihydro-3H-pyridazino[4,5-b]indol-1- yl)benzonitrile 383 [M + H]

Example 245N-ethyl-2,4-dimethyl-5-oxo-N-phenyl-6-(p-tolyl)-5,6-dihydro-4H-thieno[2′,3′:4,5]pyrrolo[2,3-d]pyridazine-8-carboxamide

Ethyl (Z)-2-azido-3-(5-methylthiophen-2-yl)acrylate

A 0° C. solution of 5-methylthiophene-2-carbaldehyde (1.0 g, 7.92 mmol)in EtOH (40 mL) was treated with ethyl azido acetate (2.0 g, 15.85mmol). After stirring for 10 min, NaOEt (1.07 g, 15.85 mmol) in EtOH (40mL) was added dropwise, and the reaction stirred at rt for 5 hrs. Thereaction was quenched with NH₄Cl solution (100 mL) at which time aprecipitate formed. The solid was collected and dried to yield ethyl(Z)-2-azido-3-(5-methylthiophen-2-yl)acrylate (0.60 g).

Ethyl 2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate

A solution of ethyl (Z)-2-azido-3-(5-methylthiophen-2-yl)acrylate (0.60g, 2.53 mmol) in toluene (20 mL) was heated at reflux for 30 min. Thesolvent was evaporated to give ethyl2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (0.50 g).

Ethyl 2,4-dimethyl-4H-thieno[3,2-b]pyrrole-5-carboxylate

Ethyl 2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (0.50 g, 2.39 mmol)was dissolved in DMF (20 mL), cooled to 0° C., and treated with NaH(60%) (0.143 g, 3.58 mmol). After 30 min, MeI (0.73 mL, 11.95 mmol) wasadded dropwise, and the reaction was stirred at rt overnight. Thereaction was quenched with NH₄Cl solution (100 mL) and extracted withEtOAc (2×100 mL). The combined organic layers were dried with Na₂SO₄ andconcentrated to give ethyl2,4-dimethyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (0.5 g).

Ethyl6-(2-ethoxy-2-oxoacetyl)-2,4-dimethyl-4H-thieno[3,2-b]pyrrole-5-carboxylate

A 0° C. solution of ethyl chloro oxoacetate (1.54 mL, 13.8 mmol) in DCE(50 mL) was treated with TiCl₄ (1.51 mL, 13.81 mmol) and stirred for 30min at rt. Ethyl 2,4-dimethyl-4H-thieno[3,2-b]pyrrole-5-carboxylate(2.80 g, 12.5 mmol) in DCE (10 mL) was added dropwise and the reactionstirred for 3 hrs. It was diluted with water (100 mL) and extracted withDCM (3×50 mL). The combined organic layers were dried with Na₂SO₄ andconcentrated to give ethyl6-(2-ethoxy-2-oxoacetyl)-2,4-dimethyl-4H-thieno[3,2-b]pyrrole-5-carboxylate(2.3 g). MS: ESI+ve, 324.1 [M+H].

Ethyl2,4-dimethyl-5-oxo-6-(p-tolyl)-5,6-dihydro-4H-thieno[2′,3′:4,5]pyrrolo[2,3-d]pyridazine-8-carboxylate

A solution of ethyl6-(2-ethoxy-2-oxoacetyl)-2,4-dimethyl-4H-thieno[3,2-b]pyrrole-5-carboxylate(1.00 g, 3.09 mmol) in HOAc (15 ml) was treated with p-tolylhydrazineHCl (0.73 g, 4.6 mmol) and heated to reflux overnight. It was dilutedwith water (100 mL) and extracted with EtOAc (3×50 mL). The combinedorganic layers were dried with Na₂SO₄ and concentrated to give ethyl2,4-dimethyl-5-oxo-6-(p-tolyl)-5,6-dihydro-4H-thieno[2′,3′:4,5]pyrrolo[2,3-d]pyridazine-8-carboxylate(1.12 g).

2,4-dimethyl-5-oxo-6-(p-tolyl)-5,6-dihydro-4H-thieno[2′,3′:4,5]pyrrolo[2,3-d]pyridazine-8-carboxylicacid

A solution of ethyl2,4-dimethyl-5-oxo-6-(p-tolyl)-5,6-dihydro-4H-thieno[2′,3′:4,5]pyrrolo[2,3-d]pyridazine-8-carboxylate(0.175 g, 0.45 mmol) in THF (6.0 ml) was treated with NaOH (0.033 g,1.37 mmol) in water (4 mL) and stirred at rt overnight. The reaction wasconcentrated, then treated with water (20 mL) and acidified with 1N HCl.The precipitate was collected and dried to yield2,4-dimethyl-5-oxo-6-(p-tolyl)-5,6-dihydro-4H-thieno[2′,3′:4,5]pyrrolo[2,3-d]pyridazine-8-carboxylicacid (0.15 g). MS: ESI+ve, 354 [M+H].

Example 245N-ethyl-2,4-dimethyl-5-oxo-N-phenyl-6-(p-tolyl)-5,6-dihydro-4H-thieno[2′,3′:4,5]pyrrolo[2,3-d]pyridazine-8-carboxamide

A solution of2,4-dimethyl-5-oxo-6-(p-tolyl)-5,6-dihydro-4H-thieno[2′,3′:4,5]pyrrolo[2,3-d]pyridazine-8-carboxylicacid (0.170 g, 0.48 mmol) in DMF (5 mL) was treated with HATU (0.274 g0.72 mmol) at 0° C. and stirred for 30 minutes. N-Ethyl aniline (0.058 g0.48 mmol) and DiEA (0.18 g, 1.44 mmol) were added and stirred at rtovernight. The reaction was diluted with water (50 mL) and crude productcollected by filtration. It was purified by chromatography (silica gel,15% EtOAc in hexane) to yieldN-ethyl-2,4-dimethyl-5-oxo-N-phenyl-6-(p-tolyl)-5,6-dihydro-4H-thieno[2′,3′:4,5]pyrrolo[2,3-d]pyridazine-8-carboxamide(0.060 g). MS: ESI+ve, 357 [M+H], ¹H NMR (DMSO-d₆) δ: 7.4 (m, 4H), 7.3(s, 1H), 7.2 (m, 3H), 6.6 (s, 2H), 4.2 (s, 3H), 3.9 (q, 2H), 2.6 (s,3H), 2.3 (s, 3H), 1.2 (t, 3H).

Representative compounds of the invention were prepared in a similarmanner to example 245 (scheme 10).

Example No. Structure IUPAC Name LCMC m/z 246.

N-ethyl-6-isopropyl-2,4- dimethyl-5-oxo-N-phenyl- 5,6-dihydro-4H-thieno[2′,3′:4,5]pyrrolo[2,3- d]pyridazine-8-carboxamide 409 [M + H]247.

N-ethyl-N-(2-fluorophenyl)- 2,4-dimethyl-5-oxo-6-(p-tolyl)-5,6-dihydro-4H- thieno[2′,3′:4,5]pyrrolo[2,3-d]pyridazine-8-carboxamide 475 [M + H]

Example 248N-isopropyl-7-oxo-N,3-diphenyl-6-(p-tolyl)-6,7-dihydroisoxazolo[3,4-d]pyridazine-4-carboxamide

Ethyl 4-(2-ethoxy-2-oxoacetyl)-5-phenylisoxazole-3-carboxylate

Ethyl 2,4-dioxo-4-phenylbutanoate (1.0 g, 4.54 mmol) was added at 0° C.to a solution of NaOEt (0.376 g, 5.52 mmol) in EtOH (20 mL). After 10min, ethyl (Z)-2-chloro-2-(hydroxyimino)acetate (0.84 g, 5.54 mmol)solution in EtOH (20 mL) was added dropwise and stirred at 25° C.overnight. The reaction was diluted with water (25 mL) and extractedwith EtOAc (3×25 mL). The combined organic layers were dried with Na₂SO₄and concentrated to give ethyl4-(2-ethoxy-2-oxoacetyl)-5-phenylisoxazole-3-carboxylate (0.85 g). MS:ESI+ve, 318.2 [M+H].

Ethyl2-oxo-2-(7-oxo-3-phenyl-6-(p-tolyl)-6,7-dihydroisoxazolo[3,4-d]pyridazin-4-yl)acetate

p-Tolylhydrazine hydrochloride (0.30 g, 1.89 mmol) was added to astirred solution of ethyl4-(2-ethoxy-2-oxoacetyl)-5-phenylisoxazole-3-carboxylate (0.50 g, 1.58mmol) in HOAc (10 mL), then heated to reflux overnight. The reaction wasdiluted with water (25 mL) and extracted with EtOAc (3×25 mL). Thecombined organic layers were dried with Na₂SO₄ and concentrated to givecrude product, which was purified by chromatography (silica gel, 10%EtOAc in hexane) to yield ethyl2-oxo-2-(7-oxo-3-phenyl-6-(p-tolyl)-6,7-dihydroisoxazolo[3,4-d]pyridazin-4-yl)acetate(0.27 g). MS: ESI+ve, 376.3 [M+H].

2-Oxo-2-(7-oxo-3-phenyl-6-(p-tolyl)-6,7-dihydroisoxazolo[3,4-d]pyridazin-4-yl)aceticacid

NaOH (55 mg, 1.38 mmol) in water (4 mL) was added to a stirred solutionof2-oxo-2-(7-oxo-3-phenyl-6-(p-tolyl)-6,7-dihydroisoxazolo[3,4-d]pyridazin-4-yl)acetate(0.26 g, 0.69 mmol) in THF (8 mL). After stirring at rt overnight, thereaction was concentrated, then treated with water (20 mL) and acidifiedwith 1N HCl. The precipitate was collected and dried to yield2-oxo-2-(7-oxo-3-phenyl-6-(p-tolyl)-6,7-dihydroisoxazolo[3,4-d]pyridazin-4-yl)aceticacid (0.20 g). MS: ESI+ve, 366.2 [M+18].

Example 248N-isopropyl-7-oxo-N,3-diphenyl-6-(p-tolyl)-6,7-dihydroisoxazolo[3,4-d]pyridazine-4-carboxamide

A solution of2-oxo-2-(7-oxo-3-phenyl-6-(p-tolyl)-6,7-dihydroisoxazolo[3,4-d]pyridazin-4-yl)aceticacid (0.18 g, 0.51 mmol) in DCM (10 mL) was treated with N-isopropylaniline (0.07 g, 0.51 mmol) and pyridine (0.6 mL). The reaction was thencooled to 0° C. and treated with POCl₃ (0.6 mL). After stirring for 1hr, the reaction was diluted with a NaHCO₃ solution (30 mL), thenextracted with EtOAc (2×30 mL). The combined organics were washed withbrine (25 mL), dried with Na₂SO₄ and concentrated to give crude product,which was purified by chromatography (silica gel, 20% EtOAc/hexane) toyieldN-isopropyl-7-oxo-N,3-diphenyl-6-(p-tolyl)-6,7-dihydroisoxazolo[3,4-d]pyridazine-4-carboxamide(0.020 g). MS: ESI+ve, 465.0 [M+H]; ¹H NMR (CDCl₃) δ: 7.99 (d, 2H), 7.7(m, 3H), 7.2 (m, 7H), 6.73 (d, 2H), 5.00 (m, 1H), 2.4 (s, 3H), 1.0 (d,6H).

Example 2494-(3-chlorophenyl)-2-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-7-methoxyphthalazin-1(2H)-one

2-bromo-1-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)ethan-1-one

A 0° C. solution of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid(1.0 g, 4.13 mmol) in DCM (20 mL) was treated with a DMF (0.1 mL) andoxalylchloride (0.8 mL, 6.9 mmol). After stirring at rt for 2 h, thereaction concentrated to dryness. The residue was dissolved in THF (10mL) and acetonitrile (10 mL), cooled to 0° C., and treated dropwise withtrimethylsilyl diazomethane (0.6 M in hexane) (5.37 mmol, 6 mL). Thereaction was stirred for 2 h at rt, diluted with water (25 mL) and sat'dNaHCO₃ (25 mL), and extracted with EtOAc (2×50 mL). The organics werewashed with brine, dried with Na₂SO₄ and concentrated. The residue at 0°C. was treated slowly with a solution of HBrHOAc (30%, 6 mL, and thereaction stirred for 0.5 h at rt. It was diluted with ice-water (50 mL)and extracted with EtOAc (2×50 mL). The organics were washed with sat'dNaHCO₃, brine, dried with Na₂SO₄ and concentrated. The crude product waspurified by chromatography (0-5% EtOAc/hexane) to yield2-bromo-1-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)ethan-1-one(0.3 g, 23%); ¹H NMR (CDCl₃) δ: 2.21-2.30 (m, 1H), 2.51-2.60 (m, 1H),3.14-3.20 (m, 1H), 3.39-3.45 (m, 1H), 3.84-3.81 (d, 1H), 3.97-3.94 (d,1H), 7.03-7.01 (m, 2H), 7.10-7.07 (m, 1H).

Example 2494-(3-chlorophenyl)-2-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-7-methoxyphthalazin-1(2H)-one

A 0° C. solution of 4-(3-chlorophenyl)-7-methoxyphthalazin-1(2H)-one(0.1 g, 0.34 mmol) in DMF (2 mL) was treated with NaH (60%) (0.012 g,0.54 mmol) and stirred for 30 min. A solution of2-bromo-1-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)ethan-1-one(0.121 g, 0.384 mmol) in DMF (2 mL) was added dropwise and the reactionstirred overnight at rt. It was diluted with water (30 mL) and extractedwith EtOAc (2×30 mL). The organics were washed with brine, dried withNa₂SO₄ and concentrated to give crude material which was purified bychromatography (30% EtOAc/hexane) to yield4-(3-chlorophenyl)-2-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-7-methoxyphthalazin-1(2H)-one(0.026 g, 16%). (ESI+ve, 524.93 [M+H]); ¹H NMR (DMSO) δ: 1.33-1.36 (q,2H), 1.59-1.62 (q, 2H), 3.95 (s, 3H), 4.94 (s, 2H), 7.33-7.35 (dd,J=1.8, 1H), 7.38-7.40 (d, J=8.4, 1H), 7.49-7.54 (m, 2H), 7.56-7.60 (m,3H), 7.61-7.65 (m, 2H), 7.67-7.68 (d, J=2.8, 1H).

Representative compounds of the invention were prepared in a similarmanner to example 249.

Example No. Structure IUPAC Name LCMS m/z 250.

2-(2-(1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-4-(3- fluorophenyl)-7-methoxyphthalazin-1(2H)-one [M + H] 251.

4-(3-chlorophenyl)-7-methoxy-2- (2-(1-(4- methoxyphenyl)cyclopropyl)-2-oxoethyl)phthalazin-1(2H)-one 477 [M + H] 252.

3-(3-(2-(1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-6- methoxy-4-oxo-3,4- dihydrophthalazin-1-yl)benzonitrile 516 [M + H]

Example 2534-(3-chlorophenyl)-2-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-7-hydroxyphthalazin-1(2H)-one

5-(benzyloxy)-2-bromobenzaldehyde

1-Bromo-5-hydroxybenzaldehyde (5.00 g, 24.9 mmol) in DMF (50 mL) wastreated with Cs₂CO₃ (12.1 g, 37.3 mmol) and stirred at 0° C. for 15minutes. Benzyl bromide (6.38 g, 37.3 mmol) was added and the reactionheated to 100° C. 4 h. After cooling to rt, it was diluted with water(100 mL) and extracted with EtOAc (2×50 mL). The organics were washedwith brine, dried with Na₂SO₄ and concentrated to give crude materialwhich was purified by chromatography (10-15% EtOAc/hexane) to yield5-(benzyloxy)-2-bromobenzaldehyde (6.8 g, 94%). (ESI+ve, 292.94 [M+H]);¹H NMR (DMSO) δ: 5.20(s, 2H), 7.29-7.36 (m, 2H), 7.42-7.47 (m, 5H),7.70-7.72 (d, J=8.8, 1H), 10.17 (s, 1H).

5-(benzyloxy)-2-bromobenzoic acid

5-(Benzyloxy)-2-bromobenzaldehyde (1.00 g, 3.42 mmol) in dioxanewater(1:1, 20 mL) was treated with KOH (0.383 g, 6.84 mmol) and KMnO₄ (0.811g, 5.13 mmol), then stirred overnight. The reaction mixture wasfiltered, washed with water, and dioxane distilled away. The aqueoussolution was acidified with 1N HCl (25 mL) to yield a precipitate whichwas filtered, washed with water, and dried to yield5-(benzyloxy)-2-bromobenzoic acid (0.715 g, 68%). (ESI+ve, 307.18[M+H]); ¹H NMR (DMSO) δ: 5.15 (s, 2H), 7.09-7.12 (m, 1H), 7.34-7.46 (m,6H), 7.59-7.61 (d, J=8.8, 1H), 13.45 (s, 1H).

3-chloro-N-methoxy-N-methylbenzamide

3-Chloro benzoic acid (20.0 g, 128 mmol) in DMF (200 mL) at 0° C. wastreated with TEA (20 mL, 134 mmol) and EDC.HCl (25.7 g, 134 mmol) andstirred under N₂ for 30 min at rt. N—O-dimethylhydroxylamine.HCl (13.7g, 140 mmol) was added and the reaction stirred overnight at rt. It wasdiluted with water (300 mL) and extracted with EtOAc (3×200 mL). Theorganics were washed with brine, dried with Na₂SO₄ and concentrated togive crude material which was purified by chromatography (0-25%EtOAc/hexane) to yield 3-chloro-N-methoxy-N-methylbenzamide (16.0 g,62%). (ESI+ve, 200.19 [M+H]); ¹H NMR (DMSO) δ: 3.26 (s, 3H), 3.54 (s,3H), 7.47-7.50 (t, 1H), 7.53-7.58 (qt, 2H), 7.59-7.61 (d, J=9.2, 1H).

5-(benzyloxy)-2-(3-chlorobenzoyl)benzoic acid

5-(Benzyloxy)-2-bromobenzoic acid (5.0 g, 10.2 mmol) in THF (50 mL) at−78° C. was treated with nBuLi (1.6 M in hexane) (12.8 mL, 20.6 mmol)and stirred for 1 h. 3-Chloro-N-methoxy-N-methylbenzamide (2.26 g, 11.3mmol) in THF (15 ml) was added, and the reaction mixture stirred for 1h, then overnight at rt. It was diluted with water (50 mL), acidifiedwith 5N HCl, and extracted with EtOAc (2×100 mL). The organics werewashed with brine, dried with Na₂SO₄ and concentrated to give5-(benzyloxy)-2-(3-chlorobenzoyl)benzoic acid (3.2 g, 53%). (ESI+ve,367.1 [M+H]).

7-(benzyloxy)-4-(3-chlorophenyl)phthalazin-1(2H)-one

5-(Benzyloxy)-2-(3-chlorobenzoyl)benzoic acid (3.2 g, 8.7 mmol) andhydrazine hydrate (0.5 mL, 9.5 mmol) in EtOH (30 mL) were heatedovernight at reflux. The EtOH was removed in vacuo, and the residuesuspended in water. The solid was filtered and dried to give crude7-(benzyloxy)-4-(3-chlorophenyl)phthalazin-1(2H)-one (0.65 g, 20%).(ESI+ve, 363.03[M+H]).

7-(benzyloxy)-4-(3-chlorophenyl)-2-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)phthalazin-1(2H)-one

7-(Benzyloxy)-4-(3-chlorophenyl)phthalazin-1(2H)-one (0.25 g, 0.687mmol) in DMF (10 mL) at 0° C. was treated with NaH (60%) (0.024 g 1.03mmol) and stirred for 30 m.2-Bromo-1-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)ethan-1-one(0.239 g, 0.75 mmol) in DMF (2 mL) was added and the reaction stirredovernight at rt. It was diluted with water (30 mL) and extracted withEtOAc (2×30 mL). The organics were washed with brine, dried with Na₂SO₄and concentrated to give crude material which was purified bychromatography (10% EtOAc/hexane) to yield7-(benzyloxy)-4-(3-chlorophenyl)-2-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)phthalazin-1(2H)-one(0.16 g, 38%). (ESI+ve, 601.08 [M+H]).

Example 2534-(3-chlorophenyl)-2-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-7-hydroxyphthalazin-1(2H)-one

7-(Benzyloxy)-4-(3-chlorophenyl)-2-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)phthalazin-1(2H)-one(0.16 g, 0.27 mmol), Pd(OAc)₂ (0.04 g, 0.178 mmol), and triethylsilane(0.062 g, 0.53 mmol) in DMC (20 mL) were stirred together at rtovernight. The reaction was diluted with water (30 mL) and extractedwith DCM (2×30 mL). The organics were washed with brine, dried withNa₂SO₄ and concentrated to give crude material which was purified bypreparative HPLC to yield4-(3-chlorophenyl)-2-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-7-hydroxyphthalazin-1(2H)-one(0.012 g, 8%). (ESI+ve, 510.83 [M+H]); ¹H NMR (DMSO) δ: 1.33-1.34 (d,2H), 1.59-1.60 (d, 2H), 4.91 (s, 2H), 7.32-7.41 (m, 3H), 7.50-7.62 (m,7H), 10.91-10.93 (d, 1H).

Representative compounds of the invention were prepared in a similarmanner to example 253.

Example No. Structure IUPAC Name LCMS m/z 254.

2-(2-(1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-4-(3- fluorophenyl)-7-hydroxyphthalazin-1(2H)-one 595 [M + H] 255.

3-(3-(2-(1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-6- hydroxy-4-oxo-3,4- dihydrophthalazin-1-yl)benzonitrile 500 [M + H]

Example 2564-(3-chlorophenyl)-2-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-7-ethoxyphthalazin-1(2H)-one

Example 253 (0.10 g, 0.19 mmol) in DMF (3 mL) at 0° C. was treated withK₂CO₃ (0.04 g, 0.29 mmol) for 30 min, then EtI (0.033 g, 0.21 mmol) wasadded and stirred overnight at rt. The reaction was diluted with water(30 mL) and extracted with EtOAc (2×20 mL). The organics were washedwith brine, dried with Na₂SO₄ and concentrated to give crude materialwhich was purified by preparative HPLC to yield4-(3-chlorophenyl)-2-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-7-ethoxyphthalazin-1(2H)-one(0.024 g, 23%). (ESI+ve, 538.9 [M+H]); ¹H NMR (DMSO) δ: 1.33-1.35 (t,2H), 1.38-1.41 (t, 3H), 1.59-1.62 (m, 2H), 4.40-4.26 (q, 2H), 4.94 (s,2H), 7.33-7.40 (m, 2H), 7.48-7.54 (m, 2H), 7.56-7.64 (m, 6H).

Representative compounds of the invention were prepared in a similarmanner to example 256.

Example No. Structure IUPAC Name LCMS m/z 257.

2-(2-(1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-4- (3-fluorophenyl)-7-ethoxyphthalazin-1(2H)-one 523 [M + H] 258.

3-(3-(2-(1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-2-oxoethyl)-6- ethoxy-4-oxo-3,4- dihydrophthalazin-1-yl)benzonitrile 530 [M + H]

Example 2592-(5-(4-cyanobenzyl)-8-methoxy-1-oxo-1,5-dihydro-2H-pyridazino[4,5-b]indol-2-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide

5-iodopyridazin-3(2H)-one

A stirred solution of 4,5-dichloropyridazin-3(2H)-one (1.0 g, 6.74 mmol)in con HI (10 mL) was heated at 120° C. for 16 h. The reaction wasdiluted with water (50 mL) and extracted with EtOAc (3×100 mL). Theorganics were washed with sodium thiosulfate (Na₂S₂O₃) and brine, driedwith Na₂SO₄ and concentrated to give crude 5-iodopyridazin-3(2H)-one(0.8 g, 222.79 [M−H]). ¹H NMR (DMSO) δ: 7.54-7.54 (s, 1H), 8.00 (s, 1H),13.27 (s, 1H).

2-(4-iodo-6-oxopyridazin-1(6H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide

To a stirred solution of 5-iodopyridazin-3(2H)-one (0.8 g, 3.61 mmol) inTHF (10 mL) was added LiHMDS (1M in THF) (5.4 mL, 5.4 mmol) dropwise at0° C. and the reaction stirred for 30 min.2-Bromo-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (1.0 g, 3.61mmol) in THF (10 mL) was added dropwise at 0° C., and the reactionmixture stirred overnight at rt. The reaction was diluted with water (50mL) and brine solution (50 mL), and a solid precipitated. The solid wasfiltered and washed with MeOH to obtain2-(4-iodo-6-oxopyridazin-1(6H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(0.6 g, 425.30 [M+H]).

2-(4-((2-bromo-4-methoxyphenyl)amino)-6-oxopyridazin-1(6H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide

Pd(OAc)₂ (0.01 g, 0.04 mmol) and BINAP (0.029 g 0.04 mmol) in toluene(10 mL) were degassed with argon for 15 min, then treated with2-bromo-4-methoxyaniline (0.30 g 1.48 mmol), Cs₂CO₃ (1.5 g 4.45 mmol)and2-(4-iodo-6-oxopyridazin-1(6H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(0.78 g 1.85 mmol). The reaction was heated to 120° C. overnight. It wasfiltered through Celite, washed with DCM (50 mL) and concentrated togive crude product, which was purified by chromatography (0-2% MeOHDCM)to yield2-(4(2-bromo-4-methoxyphenyl)amino)-6-oxopyridazin-1(6H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(0.3 g, 498.3 [M+H]).

2-(8-methoxy-1-oxo-1,5-dihydro-2H-pyridazino[4,5-b]indol-2-yl)-N-methyl-N-(methylbenzo[d]oxazol-6-yl)acetamide

2-(4-((2-Bromo-4-methoxyphenyl)amino)-6-oxopyridazin-1(6H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(0.30 g, 0.60 mmol) and NaOAc (0.12 g, 1.50 mmol) in DMA (5 mL) weredegassed with argon for 15 min. Dichlorobis(triphenylphosphine)palladium (0.004 g 0.0006 mmol) was added and the reactionheated at 180° C. for 10 minutes in a microwave. The reaction mixturewas diluted with water (100 mL) and extracted with DCM (3×50 mL). Theorganics were washed with brine (50 mL), dried with Na₂SO₄ andconcentrated, to give crude product, which was purified bycolumn-chromatography (0-2% MeOHDCM) to afford2-(8-methoxy-1-oxo-1,5-dihydro-2H-pyridazino[4,5-b]indol-2-yl)-N-methyl-N-(methylbenzo[d]oxazol-6-yl)acetamide(0.2 g, 417.90 [M+H]).

Example 2592-(5-(4-cyanobenzyl)-8-methoxy-1-oxo-1,5-dihydro-2H-pyridazino[4,5-b]indol-2-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide

2-(8-Methoxy-1-oxo-1,5-dihydro-2H-pyridazino[4,5-b]indol-2-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(0.17 g, 0.40 mmol) in THF (8 mL) at 0° C. was treated with LiHMDS (1Min THF) (0.8 mL, 0.81 mmol) and stirred for 30 min. 4-Cyanobenzylbromide (0.08 g, 0.40 mmol) in THF (10 mL) was added dropwise at 0° C.,and the resulting mixture was stirred overnight at rt. It was dilutedwith water (100 mL) and extracted with EtOAc (3×50 mL). The organicswere washed with brine (50 mL), dried with Na₂SO₄ and concentrated togive crude product, which was purified by preparative HPLC to yield2-(5-(4-cyanobenzyl)-8-methoxy-1-oxo-1,5-dihydro-2H-pyridazino[4,5-b]indol-2-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(0.03 g, 553.30 [M+H]). ¹H NMR: (400 MHz, DMSO) δ: 2.63 (s, 3H), 3.18(s, 3H), 3.85 (s, 3H), 4.73 (s, 2H), 5.89 (s, 2H), 7.15-7.18 (dd, J=2.8,8.8, 1H), 7.30-7.32 (d, J=8.4, 2H), 7.47-7.48 (d, J=7.2, 1H), 7.63-7.66(q, 2H), 7.76-7.81 (t, 3H), 7.93 (s, 1H), 8.68 (s, 1H).

Example 2602-(5-(4-fluorobenzyl)-8-methoxy-1-oxo-1,5-dihydro-2H-pyridazino[4,5-b]indol-2-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide

2-(8-Methoxy-1-oxo-1,5-dihydro-2H-pyridazino[4,5-b]indol-2-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(0.30 g, 0.71 mmol) in THF (8 mL) at 0° C. was treated with LiHMDS (1Min THF) (1.4 mL, 1.4 mmol) and stirred for 30 min. 4-Fluorobenzylbromide (0.08 g, 0.71 mmol) in THF (10 mL) was added dropwise at 0° C.,and the resulting mixture was stirred overnight at rt. It was dilutedwith water (100 mL) and extracted with EtOAc (3×50 mL). The organicswere washed with brine (50 mL), dried with Na₂SO₄ and concentrated togive crude product, which was purified by preparative HPLC to yield2-(5-(4-fluorobenzyl)-8-methoxy-1-oxo-1,5-dihydro-2H-pyridazino[4,5-b]indol-2-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide(0.03 g, 526.53 [M+H]). ¹H NMR: (400 MHz, DMSO) δ: 2.63 (s, 3H), 3.25(s, 3H), 3.84 (s, 3H), 4.73 (s, 2H), 5.75 (s, 2H), 7.13-7.18 (q, 3H),7.25-7.29 (q, 2H), 7.46-7.48 (d, J=7.6, 1H), 7.61-7.62 (d, J=2, 1H),7.70-7.77 (q, 2H), 7.93 (s, 1H), 8.71 (s, 1H).

Assays for Detecting and Measuring the Effect of Compounds onF508del-CFTR Channels CFTR-YFP High Throughput Assay-CFTR CorrectorProtocol:

This protocol is designed to selectively screen small molecule compoundsfor F508del CFTR corrector activities in the HTS YFP (yellow fluorescentprotein) flux assay. In this protocol, the cells are incubated withtesting compounds for 24 hours, washed with PBS, stimulated withforskolin and a standard potentiator, and fluorescence in each platewell is measured kinetically read on a 384-well HTS plate reader, suchas the Hamamatsu FDSS-6000.

YFP fluorescence intensity values are acquired at high speed before andafter iodide buffer is injected to the assay cells. Iodide enters thecells via active CFTR channels in the plasma membrane, and quenches theYFP fluorescence. The rate of fluorescence quenching is proportionate tothe total CFTR activity in the cell membrane. F508del CFTR correctorsincrease the number of CFTR molecules in the testing cell plasmamembrane, and thereby accelerate YFP quenching.

This method was initially developed for bench top plate readers(Galietta et al., 2001), and was adapted to the HTS format (Sui et al.Assay Drug Dev. Technol. 2010).

Fisher Rat Thyroid (FRT) cells stably expressing both human F508del CFTRand a halide-sensitive yellow fluorescent protein (YFP-H148Q/I152L25,22) (Galietta et al. Am. J. Physiol Cell Physiol 281(5), C1734, 2001)were cultured on plastic surface in Coon's modified Ham's F12 mediumsupplemented with FBS10%, L-glutamine 2 mM, penicillin 100 U/ml, andstreptomycin 100 μg/ml. G418 (0.75-1.0 mg/ml) and zeocin (3.2 ug/ml)were used for selection of FRT cells expressing F508del CFTR and YFP.For primary screening, FRT cells were plated into 384-well black wall,transparent bottom microtiter plates (Costar; Corning Inc.) at a celldensity of 20,000-40,000 per well. Test compound was applied to thecells at varying concentrations ranging from 2 nM-40 μM in either a2-fold or 3-fold dilution series. Cells were incubated in a cell cultureincubator at 37° C. with 5% CO₂ for 24-26 h. Assay plates were washedwith DPBS media (Thermo, cat# SH30028.02) to remove unbound cells andcompound. Stimulation media (25 μL) containing 20 μM Forskolin & 30 μMP3 [6-(Ethyl-phenyl-sulfonyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid 2-methoxy-benzylamide] in Hams F-12 coon's modified media was addedto the plate wells and incubated at room temperature for 60-120 min. 25μL of HEPES-PBS-I buffer (10 mM HEPES, 1 mM MgCl₂, 3 mM KCl, 1 mM CaCl₂,150 mM NaI) was then added and fluorescence quench curves (Excitation500 nmEmission 540 nm; exposure 136 ms) were immediately recorded on anFDSS-6000 plate reader (Hamamatsu). Quench rates were derived from leastsquares fitting of the data as described by Sui et al (2010).

CFTR-YFP High Throughput Assay-CFTR Potentiator Protocol:

This protocol is designed to selectively screen small molecule compoundsfor F508del CFTR potentiator activities in the HTS YFP flux assay. Suchcompounds act acutely to stimulate CFTR already expressed on themembrane surface. In this protocol, the cells are incubated at 27° C.for 24 hours to homogeneously boost F508del CFTR expression in the cellmembrane (low temperature correction), washed with PBS, treated withtest compound, and CFTR activity is stimulated with forskolin for 1-2hr. Measurement of ion flux is initiated by addition ofiodide-containing buffer, and YFP quenching is kinetically recordedusing a 384-well HTS plate reader, such as the Hamamatsu FDSS-6000.

YFP fluorescence intensity values are acquired at high speed over a 1min time course before and after iodide buffer is injected to the assaycells. Iodide enters the cells via active CFTR channels in the plasmamembrane, and quenches the YFP fluorescence. The rate of fluorescencequenching is proportionate to total CFTR activity in the cell membrane.F508del-CFTR potentiators increase CFTR open probability orCFTR-mediated ion conductivity, and this enhanced CFTR mediated iodideflux in the test cell plasma membrane accelerates YFP quenching.

This method was initially developed for bench top plate readers(Galietta et al., 2001), and was adapted to the HTS format (Sui et al.Assay Drug Dev. Technol. 2010).

Fisher Rat Thyroid (FRT) cells stably expressing both human F508del CFTRand a halide-sensitive yellow fluorescent protein (YFP-H148Q/I152L25,22) (Galietta et al., Am. J. Physiol Cell Physiol 281(5), C1734,2001) were cultured on plastic surface in Coon's modified Ham's F12medium supplemented with FBS10%, L-glutamine 2 mM, penicillin 100 U/ml,and streptomycin 100 μg/ml. G418 (0.75-1.0 mg/ml) and zeocin (3.2 ug/ml)were used for selection of FRT cells expressing F508del CFTR and YFP.For primary screening, FRT cells were plated into 384-well black wall,transparent bottom microtiter plates (Costar; Corning Inc.) at a celldensity of 20,000-40,000 per well. Cells were incubated in a cellculture incubator at 37° C. with 5% CO₂ for 24-26 h. Assay plates werewashed with DPBS media (Thermo, cat# SH30028.02) to remove unboundcells. Test compound was applied to the cells at varying concentrationsranging from 2 nM-40 μM in either a 2-fold or 3-fold dilution series inDPBS and stimulated with 20 μM Forskolin (final concentration) in HamsF-12 coon's modified media. Plates were incubated at room temperaturefor 60-120 min. 25 μL of HEPES-PBS-I buffer (10 mM HEPES, 1 mM MgCl₂, 3mM KCl, 1 mM CaCl₂, 150 mM NaI) was then added and fluorescence quenchcurves (Excitation 500 nmEmission 540 nm; exposure 136 ms) wereimmediately recorded on an FDSS-6000 plate reader (Hamamatsu). Quenchrates were derived from least squares fitting of the data as describedby Sui et al (2010).

REFERENCES

-   Galietta, L. J., Jayaraman, S., and Verkman, A. S. Cell-based assay    for high-throughput quantitative screening of CFTR chloride    transport agonists. Am. J. Physiol Cell Physiol 281(5), C1734, 2001.-   Sui J, Cotard S, Andersen J, Zhu P, Staunton J, Lee M, Lin S. (2010)    Optimization of a Yellow fluorescent protein-based iodide influx    high-throughput screening assay for cystic fibrosis transmembrane    conductance regulator (CFTR) modulators. Assay Drug Dev Technol.    2010 December; 8(6):656-68.    Cell Culture:

Primary CF airway epithelial cells were obtained from the UNC CysticFibrosis Tissue Procurement and Cell Culture Core. The cells are grownat 37° C. in a Heracell 150i incubator using growth media (BEGM,Fischer). Cells were then transferred to differentiation media (ALI,UNC) for a minimum of 4 weeks on coated Costar snapwells. Two daysbefore the Ussing assay the mucus on the apical surface of the cells wasaspirated after incubating with 200 μL of differentiation Media for atleast thirty (30) minutes. One day before the Ussing assay, testcompounds were applied to the basolateral surface of the cells atvarious test concentrations (n=3 or n=4 replicates per test condition).

Ussing Assay

Ussing chambers and the associated voltage clamp were obtained fromPhysiologic Instruments, (San Diego, Calif.). Ussing assays wereperformed at the 37° C. HEPES buffered physiological saline (HB-PS) wasused in apical and basolateral chambers with glucose added to thebasolateral solutions. Epithelia were equilibrated for 15 minutes in thechambers while the bath temperature and transepithelial voltage werestabilized and adjusted before application of voltage clamp.

Compounds were added in the following order.

Step Chamber 3.0 uM Benzamil for 20 minutes apical addition only 10 uMForskolin for 20 minutes apical + basolateral addition 10 uM Genesteinfor 20 minutes apical + basolateral addition 10 uM CFTR-172 for 20minutes apical + basolateral addition 20 uM Bumetanide for 30 minutesbasolateral addition only

The short circuit current and transepithelial resistances(typically >300 Ω-cm2) from each chamber was recorded every 10 secondson stored on a PC using Acquire and Analyze (Physiologic Instruments).

Analysis

Efficacy of test compounds was compared using the average of theforskolin response and the CFTR-172 inhibited current response of thetest compound divided by the average of the forskolin response and theCFTR-172 inhibited current elicited by the positive control. Normalizedscores were tabulated for all compounds and concentrations.

TABLE I Example % Efficacy EC₅₀ 1. + ++ 2. + +++ 3. ++ + 4. ++ + 5. ++++ 6. ++ +++ 7. ++ + 8. ++ +++ 9. + +++ 10. + + 11. ++ ++ 12. ++ + 13.++ ++ 14. ++ + 15. + + 16. ++ +++ 17. ++ +++ 18. +++ ++ 19. +++ ++ 20.++ + 21. +++ +++ 22. +++ +++ 23. +++ +++ 24. ++ +++ 25. ++ ++ 26. ++ +++27. ++ +++ 28. ++ +++ 29. ++ +++ 30. ++ +++ 31. ++ +++ 32. + +++ 33. +++++ 34. ++ +++ 35. ++ +++ 36. ++ +++ 37. ++ +++ 38. ++ +++ 39. ++ + 40.++ +++ 41. ++ +++ 42. + + 43. + + 44. ++ ++ 45. +++ +++ 46. ++ +++ 47.++ +++ 48. ++ +++ 49. +++ +++ 50. +++ +++ 51. ++ +++ 52. ++ +++ 53. +++++ 54. ++ +++ 55. ++ +++ 56. ++ +++ 57. ++ +++ 58. ++ +++ 59. ++ ++ 60.++ +++ 61. ++ +++ 62. ++ +++ 63. +++ +++ 64. ++ +++ 65. +++ +++ 66. ++++++ 67. ++ +++ 68. ++ +++ 69. +++ +++ 70. ++ +++ 71. ++ +++ 72. +++ +++73. ++ +++ 74. ++ +++ 75. +++ +++ 76. +++ +++ 77. +++ ++ 78. ++ +++ 79.+++ +++ 80. ++ ++ 81. +++ +++ 82. ++ +++ 83. ++ +++ 84. ++ +++ 85. ++++++ 86. +++ +++ 87. +++ +++ 88. +++ +++ 89. +++ +++ 90. +++ +++ 91. ++++++ 92. +++ +++ 93. +++ +++ 94. +++ +++ 95. +++ +++ 96. +++ +++ 97. ++++++ 98. +++ +++ 99. +++ +++ 100. +++ +++ 101. +++ +++ 102. +++ +++ 103.+++ +++ 104. +++ +++ 105. +++ +++ 106. +++ +++ 107. +++ +++ 108. +++ +++109. +++ +++ 110. +++ +++ 111. +++ +++ 112. +++ +++ 113. +++ +++ 114.+++ +++ 115. +++ +++ 116. +++ +++ 117. +++ +++ 118. +++ +++ 119. +++ +++120. +++ +++ 121. +++ +++ 122. +++ +++ 123. +++ +++ 124. ++ ++ 125. +++++ 126. ++ +++ 127. ++ +++ 128. ++ ++ 129. ++ ++ 130. ++ ++ 131. ++ +++132. ++ +++ 133. ++ +++ 134. ++ +++ 135. ++ +++ 136. ++ +++ 137. ++ +++138. + + 139. ++ ++ 140. ++ +++ 141. ++ +++ 142. ++ +++ 143. ++ +++ 144.+++ ++ 145. ++ +++ 146. ++ +++ 147. ++ +++ 148. ++ +++ 149. ++ +++ 150.++ +++ 151 ++ +++ 152. ++ +++ 153. ++ +++ 154. ++ +++ 155. ++ +++ 156.++ +++ 157. ++ +++ 158. ++ +++ 159. ++ +++ 160. ++ +++ 161. ++ +++ 162.++ + 163. ++ + 164. ++ + 165. ++ +++ 166. ++ +++ 167. ++ +++ 168. ++ +++169. ++ +++ 170. ++ +++ 171. + + 172. + ++ 173. + + 174. ++ +++ 175.++ + 176. ++ +++ 177. ++ +++ 178. ++ +++ 179. ++ + 180. + +++ 181. +++++ 182. ++ +++ 183. ++ +++ 184. ++ + 185. ++ +++ 186. + +++ 187. ++ +188. ++ + 189. ++ + 190. ++ +++ 191. ++ + 192. ++ +++ 193. ++ +++ 194.++ + 195. ++ +++ 196. +++ + 197. ++ + 198. ++ +++ 199. + + 200. ++ +++201. ++ +++ 202. ++ +++ 203. ++ +++ 204. ++ +++ 205. ++ +++ 206. ++ +++207. ++ +++ 208. + +++ 209. ++ +++ 210. ++ +++ 211. ++ +++ 212. ++ +++213. ++ +++ 214. ++ +++ 215. ++ +++ 216. ++ +++ 217. + + 218. +++ +++219. + ++ 220. ++ +++ 221. ++ +++ 222. ++ + 223. ++ + 224. ++ + 225.++ + 226. ++ + 227. ++ +++ 228. ++ +++ 229. ++ +++ 230. ++ +++ 231. +++++ 232. ++ +++ 233. ++ +++ 234. ++ +++ 235. + + 236. + + 237. + + 238.++ +++ 239. ++ + 240. ++ + 241. ++ +++ 242. ++ + 243. ++ +++ 244. ++ +++245. + +++ 246. ++ + 247. ++ + 248. + +++ 249. +++ +++ 250. ++ +++ 251.++ +++ 252. +++ +++ 253. 254. 255. 256. 257. 258. 259. +++ +++ 260. ++++++ CFTR-YFP High Throughput Assay; The following meanings apply: %Efficacy is reported as the EMax normalized to the positivecontrol.“+++” refers to EMax > 80%, “++” refers to a range of 80%-30%,“+” refers to a range of 30%-10%. EC₅₀: “+++” refers to EC₅₀ < 10 M,“++” refers to EC50 range of between 10-20 M, “+” refers to EC₅₀ > 20μM.

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. All other published references, documents,manuscripts and scientific literature cited herein are herebyincorporated by reference.

What is claimed:
 1. A compound of Formula V:

or a pharmaceutically acceptable salt, or ester thereof; wherein

represents a single or double bond; Cy₁ is an aryl or substituted arylgroup having one, two or three rings; Cy₂ is an aryl or substituted arylgroup having one, two or three rings; A₁ is —[C(R₁₀₀)(R₁₀₁)]_(n)—,—C(O)—, —C(S)—, —S(O)—, —C(O)N(R₁₀₀)—, —S(O)₂N(R₁₀₀)—, —S(O)₂—,carbocycle, substituted carbocycle, heterocycle, substitutedheterocycle, aromatic, substituted aromatic, heteroaromatic orsubstituted heteroaromatic; wherein each R₁₀₀ and R₁₀₁ is independentlyhydrogen, deuterium, halogen, alkyl, substituted alkyl, heteroalkyl,substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aliphatic, substituted aliphatic, aryl, substitutedaryl, —OR₂₀₀, —SR₂₀₀, —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂, or —S(O)₂R₂₀₀; whereinR₂₀₀ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;alternatively two R₁₀₀ and R₁₀₁ groups together with the atoms to whichthey are attached and any intervening atoms form an optionallysubstituted 3, 4, 5, 6 or 7 membered ring; Cy₃ is an aryl, substitutedaryl, carbocycle, substituted carbocycle, heterocyclyl, substitutedheterocyclyl, heteroaryl, or substituted heteroaryl group having one,two or three rings; Cy₅ is a spiro attached C₃-C₆ carbocycle; A₂ is—[C(R₁₀₀)(R₁₀₁)]_(n)—, —C(O)—, —C(S)—, —S(O)—, or —C(O)N(R₁₀₀)—, —or—S(O)₂—, A₃ is absent —[C(R₁₀₀)(R₁₀₁)]_(n)—, —C(O)—, —C(S)—, —S(O)—,—C(O)N(R₁₀₀)—, —or S(O)₂ and each n is 0, 1, 2, 3, 4, 5, 6 or
 7. 2. Thecompound of claim 1 having the formula:

or a pharmaceutically acceptable salt thereof.
 3. A compound accordingto claim 2, wherein Cy₂ is

wherein q is 0, 1, 2, 3 or 4; each R₁₀₂ is independently hydrogen,deuterium, halogen, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic,carbocycle, substituted carbocycle, aryl, substituted aryl, —OR₁₀₀,—SR₁₀₀, —NR₁₀₀R₁₀₁, —C(O)R₁₀₀, —C(O)OR₁₀₀, —C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀, —S(O)R₁₀₀, —SR₁₀₀, —S(O)₂N(R₁₀₀)R₁₀₁ —CF₃, —CN, —NO₂,or —N₃; alternatively two R₁₀₂ groups together with the atoms to whichthey are attached and any intervening atoms may form an additionaloptionally substituted 3, 4, 5, 6 or 7 membered ring; or apharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising a compound according to claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 5. A method for treating cysticfibrosis or a symptom thereof, comprising the step of administering to asubject in need thereof a therapeutically effective amount of a compoundaccording to claim
 1. 6. The compound of claim 1 wherein Cy₅ iscyclopropyl or cyclobutyl.
 7. The compound of claim 1 wherein Cy₂ issubstituted with —OR₂₀₀, —SR₂₀₀, —C(O)R₂₀₀, —C(O)N(R₂₀₀)₂, or —S(O)₂R₂₀₀wherein R₂₀₀ is hydrogen, C₁—C₆ alkyl, C₂—C₆ alkenyl, or C₂-C₆ alkynyl.8. The compound of claim 1 selected from the following table, or apharmaceutically acceptable salt thereof:


9. The compound of claim 8 having the formula or a pharmaceuticallyacceptable salt thereof:


10. The compound of claim 2, or a pharmaceutically acceptable saltthereof, wherein Cy₃ is selected from:

wherein each R₃₀, R₃₁, R₃₂ and R₃₃ is independently selected fromhydrogen, deuterium, halogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aliphatic,substituted aliphatic, carbocycle, substituted carbocycle, aryl,substituted aryl, —OR₁₀₀, —SR₁₀₀, —NR₁₀₀R₁₀₁, —C(O)R₁₀₀, —C(O)R₁₀₀,—C(O)NR₁₀₀R₁₀₁, —N(R₁₀₀)C(O)R₁₀₁, —S(O)₂R₁₀₀, —S(O)R₁₀₀, —SR₁₀₀,—S(O)₂N(R₁₀₀)R₁₀₁ —CF₃, —CN, —NO₂, —N₃; alternatively two R₃₀, R₃₁, R₃₂or R₃₃ groups together with the atoms to which they are attached and anyintervening atoms form an optionally substituted 3, 4, 5, 6 or 7membered ring; and, q is 0, 1, 2, 3, or 4; or a pharmaceuticallyacceptable salt thereof.
 11. The compound of claim 1 wherein A₁ is[C(R₁₀₀)(R₁₀₁)]_(n)—; or a pharmaceutically salt thereof.
 12. Thecompound of claim 11 wherein A₂ is —C(O)—; or a pharmaceuticallyacceptable salt thereof.
 13. The compound of claim 10 wherein Cy₃ is:

or a pharmaceutically acceptable salt thereof.
 14. The pharmaceuticalcomposition according to claim 4 further comprising one or morecompounds compound selected from Gentamicin, Ataluren, Ivacaftor(Kalydeco) and VX-809 or a combination thereof.